U.S. patent number 5,885,999 [Application Number 08/786,522] was granted by the patent office on 1999-03-23 for serine derivatives and their use as therapeutic agents.
This patent grant is currently assigned to Merck Sharp & Dohme Ltd.. Invention is credited to Jason Matthew Elliott, Angus Murray MacLeod, Graeme Irvine Stevenson.
United States Patent |
5,885,999 |
Elliott , et al. |
March 23, 1999 |
Serine derivatives and their use as therapeutic agents
Abstract
The present invention relates to compounds of formula (I):
##STR1## wherein m is zero, 1 or 2; and n is zero or 1, with the
proviso that the sum total of m+n is 1 or 2; R.sup.1 represents
phenyl; naphthyl; benzhydryl; or benzyl, where the naphthyl group
or any phenyl moiety may be substituted; R.sup.2 represents
hydrogen; phenyl; heteroaryl selected from indazolyl, thienyl,
furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; naphthyl;
benzhydryl; or benzyl; wherein each heteroaryl, the naphthyl group
and any phenyl moiety may be substituted; R.sup.3 and R.sup.4 each
independently represents hydrogen or C.sub.1-6 alkyl or R.sup.3 and
R.sup.4 together are linked so as to form a C.sub.1-3 alkylene
chain; Q represents CR.sup.5 R.sup.6 or NR.sup.5 ; X and Y each
independently represents hydrogen, or together form a group .dbd.O;
and Z represents a bond, O, S, SO, SO.sub.2, NR.sup.c or
--(CR.sup.c R.sup.d)--, where R.sup.c and R.sup.d each
independently represent hydrogen or C.sub.1-6 alkyl; or a
pharmaceutically acceptable salt thereof. The compounds are of
particular use in the treatment or prevention of pain,
inflammation, migraine, emesis and postherpetic neuralgia.
Inventors: |
Elliott; Jason Matthew
(Knockholt, GB2), MacLeod; Angus Murray (Bishops
Stortford, GB2), Stevenson; Graeme Irvine (Saffron
Walden, GB2) |
Assignee: |
Merck Sharp & Dohme Ltd.
(Hoddesdon, GB2)
|
Family
ID: |
10787723 |
Appl.
No.: |
08/786,522 |
Filed: |
January 21, 1997 |
Foreign Application Priority Data
|
|
|
|
|
Jan 29, 1996 [GB] |
|
|
9601724 |
|
Current U.S.
Class: |
514/266.22;
514/319; 544/298; 546/192; 546/206; 546/205; 544/300;
514/266.2 |
Current CPC
Class: |
C07D
213/74 (20130101); C07D 239/42 (20130101); C07D
211/16 (20130101); C07D 211/28 (20130101); C07D
211/26 (20130101); C07D 401/04 (20130101); C07D
211/64 (20130101); C07D 295/185 (20130101); C07D
221/20 (20130101); C07D 491/10 (20130101); C07D
211/22 (20130101) |
Current International
Class: |
C07D
495/20 (20060101); C07D 491/00 (20060101); C07D
295/185 (20060101); C07D 211/00 (20060101); C07D
211/16 (20060101); C07D 211/28 (20060101); C07D
211/22 (20060101); C07D 211/26 (20060101); C07D
239/00 (20060101); C07D 239/42 (20060101); C07D
213/00 (20060101); C07D 213/74 (20060101); C07D
211/64 (20060101); C07D 221/20 (20060101); C07D
221/00 (20060101); C07D 401/00 (20060101); C07D
401/04 (20060101); C07D 295/00 (20060101); C07D
491/10 (20060101); C07D 495/00 (20060101); C07D
239/02 (); C07D 211/06 (); A61K 031/445 (); A61K
031/505 () |
Field of
Search: |
;546/192,205,206
;514/319,258 ;544/298,300 |
References Cited
[Referenced By]
U.S. Patent Documents
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5346907 |
September 1994 |
Kerwin, Jr. et al. |
5536716 |
July 1996 |
Chen et al. |
|
Foreign Patent Documents
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0 360 390 |
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Mar 1990 |
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EP |
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675122 |
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Oct 1995 |
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EP |
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WO 94/29309 |
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Dec 1994 |
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WO |
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95/15319 |
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Jun 1995 |
|
WO |
|
96/05203 |
|
Feb 1996 |
|
WO |
|
96/39384 |
|
Dec 1996 |
|
WO |
|
97/15573 |
|
May 1997 |
|
WO |
|
Primary Examiner: Clardy; S. Mark
Assistant Examiner: Qazi; Sabiha N.
Attorney, Agent or Firm: Durette; Philippe L. Winokur;
Melvin
Claims
We claim:
1. A compound of formula (I): ##STR12## wherein m is zero, 1 or
2;
n is zero or 1, with proviso that the sum total of m+n is 2;
R.sup.1 represents unsubstituted phenyl or phenyl substituted by 1,
2 or 3 groups selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4 alkyl, --O(CH.sub.2).sub.p O-- where p is 1 or
2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl,
OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b,
NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, COR.sup.a, CO.sub.2
R.sup.a or CONR.sup.a R.sup.b, where R.sup.a and R.sup.b each
independently represent hydrogen, C.sub.1-6 alkyl, phenyl or
trifluoromethyl; naphthyl; benzhydryl; or benzyl, where the
naphthyl group or each phenyl moiety of benzyl and benzhydryl may
be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or
trifluoromethyl;
R.sup.2 represents hydrogen; unsubstituted phenyl or phenyl
substituted by 1, 2 or 3 groups selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4 alkyl, --O(CH.sub.2).sub.p O-- where
p is 1 or 2, halogen, cyano, nitro, trifluoromethyl,
trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a,
NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b,
COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b, where R.sup.a
and R.sup.b are as previously defined; heteroaryl selected from
indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and
quinolinyl; naphthyl; benzhydryl; or benzyl; wherein each
heteroaryl, the naphthyl group and each phenyl moiety of benzyl and
benzhydryl may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
halogen or trifluoromethyl;
R.sup.3 and R.sup.4 each independently represents hydrogen or
C.sub.1-6 alkyl or R.sup.3 and R.sup.4 together are linked so as to
form a C.sub.1-3 alkylene chain;
Q represents CR.sup.5 R.sup.6 ;
X and Y each independently represents hydrogen, or together form a
group .dbd.O;
Z represents a bond, O, S, SO, SO.sub.2, NR.sup.c or --(CR.sup.c
R.sup.d)--, where R.sup.c and R.sup.d each independently represent
hydrogen or C.sub.1-6 alkyl;
R.sup.5 represents C.sub.1-3 alkyl substituted by a group selected
from OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a
R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, NR.sup.a
SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a
R.sup.b, where R.sup.a and R.sup.b are as previously defined;
unsubstituted phenyl; phenyl substituted by 1, 2 or 3 groups
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl,
--O(CH.sub.2).sub.p O-- where p is 1 or 2, halogen, cyano, nitro,
trifluoromethyl, trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a,
SO.sub.2 R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a
CO.sub.2 R.sup.b, NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2
R.sup.a or CONR.sup.a R.sup.b, or C.sub.1-3 alkyl substituted by a
group selected from OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2
R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2
R.sup.b, NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or
CONR.sup.a R.sup.b, where R.sup.a and R.sup.b are as previously
defined; benzimidazol-1-yl; 2-keto-benzimidazol-1-yl; or heteroaryl
selected from pyrindinyl, pyridazinyl, pyrimidinyl and pyrazinyl,
wherein each heteroaryl may be substituted by C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, halogen or trifluoromethyl;
R.sup.6 represent hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4 alkyl, halogen, cyano, nitro, trifluoromethyl,
trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a,
NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b,
NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a, CONR.sup.a
R.sup.b, or C.sub.1-3 alkyl substituted by a group selected from
OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b,
NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, NR.sup.a SO.sub.2
R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b, where
R.sup.a and R.sup.b are as previously defined;
or R.sup.5 and R.sup.6 together are linked so that CR.sup.5 R.sup.6
represents a group selected from ##STR13## or a pharmaceutically
acceptable salt thereof.
2. A process for the preparation of a compound as claimed in claim
1 which comprises:
(A), where X and Y are both hydrogen, reacting a compound of
formula (II): ##STR14## wherein R, R.sup.1, R.sup.3, R.sup.4,
R.sup.5, Q, Z, m and n are as defined in claim 1, with an aldehyde
of formula R.sup.2 --CHO in the presence of a reducing agent;
or
(B), where X and Y together form a group .dbd.O, reacting a
compound of formula (II) with an acyl halide of formula R.sup.2
--COHal where Hal is a halogen atom; or
(C), reacting a compound of formula (III) with a compound of
formula (IV): ##STR15## wherein R, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, Q, X, Y, Z, m and n are as defined in claim 1;
or
(D), interconversion of one compound of formula (I) into another
compound of formula (I);
each process being followed, where necessary, by the removal of any
protecting group where present;
and when the compound of formula (I) is obtained as a mixture of
enantiomers or diastereoisomers, optionally resolving the mixture
to obtain the desired enantiomer;
and/or, if desired, converting the resulting compound of formula
(I) or a salt thereof, into a pharmaceutically acceptable salt
thereof.
3. A compound as claimed in claim 1 wherein R.sup.1 represents
unsubstituted phenyl or phenyl substituted by one or two groups
selected from C.sub.1-6 alkyl, halogen, and trifluoromethyl.
4. A compound as claimed in claim 1 wherein R.sup.2 represents
unsubstituted or substituted phenyl, 5-membered heteroaryl,
6-membered heteroaryl, quinolinyl, naphthyl, or benzhydryl.
5. A compound as claimed in claim 1 wherein R.sup.3 and R.sup.4
each independently represent hydrogen.
6. A compound a claimed in claim 1 wherein R.sup.5 represents
C.sub.1-3 alkyl substituted by a group selected from NR.sup.a
COR.sup.b, NR.sup.a SO.sub.2 R.sup.b or CO.sub.2 R.sup.a, where
R.sup.a and R.sup.b are as defined in claim 1; unsubstituted
phenyl; phenyl substituted by a group selected from C.sub.1-6
alkyl, halogen, cyano, nitro, OR.sup.a, NR.sup.a R.sup.b, NR.sup.a
SO.sub.2 R.sup.b or C.sub.1-3 alkyl substituted by NR.sup.a
R.sup.b, NR.sup.a COR.sup.b or NR.sup.a SO.sub.2 R.sup.b, where
R.sup.a and R.sup.b are as defined in claim 1;
2-keto-benzimidazol-1-yl; pyridinyl; or pyrimidinyl.
7. A compound as claimed in claim 1 wherein R.sup.6 represents
hydrogen, cyano, NR.sup.a COR.sup.b, CO.sub.2 R.sup.b or C.sub.1-3
alkyl substituted by OR.sup.a, NR.sup.a COR.sup.b or NRSO.sub.2
R.sup.b, where R.sup.a and R.sup.b are as defined in claim 1.
8. A compound as claimed in claim 1 wherein Q is CR.sup.5 R.sup.6,
wherein the group CR.sup.5 R.sup.6 is selected from: ##STR16##
9. A compound as claimed in claim 1 wherein X and Y are both
hydrogen atoms.
10. A compound as claimed in claim 1 wherein Z is an oxygen
atom.
11. A compound as claimed in claim 1 of formula (Ia): ##STR17##
wherein m, n, Q, X and Y are as defined in claim 1;
Z' is O, S or --CH.sub.2 --;
R.sup.20 and R.sup.21 independently represent hydrogen, C.sub.1-6
alkyl, halogen, trifluoromethyl, OR.sup.a, or NR.sup.a R.sup.b,
where R.sup.a and R.sup.b are as defined in claim 1; and
R.sup.22 and R.sup.23 independently represent hydrogen or
halogen;
or a pharmaceutically acceptable salt thereof.
12. A compound as claimed in claim 1 of formula (Ib): ##STR18##
wherein m, n, Q, X and Y are as defined in claim 1;
Z" is O or --CH.sub.2 --;
R.sup.24 and R.sup.25 independently represent hydrogen or chlorine;
and
R.sup.26 and R.sup.27 independently represent hydrogen or chlorine,
with the proviso that at least one of R.sup.26 and R.sup.27
represents chlorine;
or a pharmaceutically acceptable salt thereof.
13. A compound selected from:
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-keto-1-benzim
idazolinyl)piperidine;
(S)-1'-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]spiro[1H-indene-1,
4'-piperidine];
(S)-N-({1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide;
(S)-1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-(methanesulfonam
idomethyl)-4-phenylpiperidine;
(S)-1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperidine
;
(S)-N-{1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperid
in-4-yl}acetamide;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-cyano-4-phenylpi
peridine;
(S)-methyl
1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperidine-4-
carboxylate;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methoxyphenyl
)piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(methanesulfo
namido)phenyl]piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-{2-[N-(methyl)me
thanesulfonamido]phenyl}piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(methanesulfonam
idomethyl)-4-phenylpiperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(N-phenylmethane
sulfonamidomethyl)piperidine;
(S)-N-({1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide;
(S)-N-({1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperidin-4-yl}
methyl)-N-phenylacetamide;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
2'(1'H)-quinazolin]-4'(3'H)-one];
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-2,3-dihydrospiro[
1H-indene-1,4'-piperidine];
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
6'-[6'H]thieno[2,3-b]thiopyran]-4'(5'H)-one];
(2S,
3'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benz
opyran-2,3'-piperidine]-4-(3H)-one;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-6-methoxyspiro[2H
-1-benzopyran-2,4'-piperidine]-4-(3H)-one;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methylphenyl)
piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-hydroxymethyl-4-
phenylpiperidine;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidin]-4-(3H)-one;
(2S,
4'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-3,4-dihydrospi
ro[2H-1-benzopyran-2,4'-piperidine]-4-ol;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidine];
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound as claimed
in claim 1 in association with a pharmaceutically acceptable
carrier or excipient.
15. A method for the treatment or prevention of physiological
disorders associated with an excess of tachykinins, which method
comprises administration to a patient in need thereof of a
tachykinin reducing amount of a compound according to claim 1.
16. A method according to claim 15 for the treatment or prevention
of pain or inflammation.
17. A method according to claim 15 for the treatment or prevention
of migraine.
18. A method according to claim 15 for the treatment or prevention
of emesis.
19. A method according to claim 15 for the treatment or prevention
of postherpetic neuralgia.
Description
This invention relates to a class of azacyclic compounds, which are
useful as tachykinin antagonists. More particularly, the compounds
of the invention comprise a substituted piperidine or piperazine
moiety and a substituted serine derived moiety.
The tachykinins are a group of naturally occurring peptides found
widely distributed throughout mammalian tissues, both within the
central nervous system and in peripheral nervous and circulatory
systems.
The tachykinins are distinguished by a conserved carboxyl-terminal
sequence:
At present, there are three known mammalian tachykinins referred to
as substance P, neurokinin A (NKA, substance K, neuromedin L) and
neurokinin B (NKB, neuromedin K) (for review see J. E. Maggio,
Peptides (1985) 6 (suppl. 3), 237-242). The current nomenclature
designates the three tachykinin receptors mediating the biological
actions of substance P, NKA and NKB as the NK.sub.1, NK.sub.2 and
NK.sub.3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in
pain, headache, especially migraine, Alzheimer's disease, multiple
sclerosis, attenuation of morphine withdrawal, cardiovascular
changes, oedema, such as oedema caused by thermal injury, chronic
inflammatory diseases such as rheumatoid arthritis,
asthma/bronchial hyperreactivity and other respiratory diseases
including allergic rhinitis, inflammatory diseases of the gut
including ulcerative colitis and Crohn's disease, ocular injury and
ocular inflammatory diseases, proliferative vitreoretinopathy,
irritable bowel syndrome and disorders of bladder function
including cystitis and bladder detruser hyper-reflexia is reviewed
in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.
A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.
Pharmacol. (1993) 13, 23-93.
For instance, substance P is believed inter alia to be involved in
the neurotransmission of pain sensations [Otsuka et al, "Role of
Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic
Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation
Symposium 91, 13-34 (published by Pitman) and Otsuka and
Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS
(1987) 8, 506-510], specifically in the transmission of pain in
migraine (B. E. B. Sandberg et al, J. Med Chem, (1982) 25, 1009)
and in arthritis [Levine et al in Science (1984) 226, 547-549].
Tachykinins have also been implicated in gastrointestinal (GI)
disorders and diseases of the GI tract such as inflammatory bowel
disease [Mantyh et al in Neuroscience (1988) 25(3), 817-37 and D.
Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier
Scientific Publishers, Amsterdam (1987) page 85)] and emesis [F. D.
Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is
also hypothesised that there is a neurogenic mechanism for
arthritis in which substance P may play a role [Kidd et al "A
neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11
Nov. 1989 and Groblad et al, "Neuropeptides in Synovium of Patients
with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol.
(1988) 15(12), 1807-10]. Therefore, substance P is believed to be
involved in the inflammatory response in diseases such as
rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et
al, Arthritis and Rheumatism (1990) 33, 1023-8]. Other disease
areas where tachykinin antagonists are believed to be useful are
allergic conditions [Hamelet et al, Can. J. Pharmacol. Physiol.
(1988) 66, 1361-7], immunoregulation [Lotz et al, Science (1988)
241, 1218-21 and Kimball et al, J. Immunol. (1988) 141(10), 3564-9]
vasodilation, bronchospasm, reflex or neuronal control of the
viscera [Mantyh et al, PNAS (1988) 85, 3235-9] and, possibly by
arresting or slowing .beta.-amyloid-mediated neurodegenerative
changes [Yankner et al, Science (1990) 250, 279-82] in senile
dementia of the Alzheimer type, Alzheimer's disease and Down's
Syndrome.
Tachykinin antagonists may also be useful in the treatment of small
cell carcinomas, in particular small cell lung cancer (SCLC)
[Langdon et al, Cancer Research (1992) 52, 4554-7].
Substance P may also play a role in demyelinating diseases such as
multiple sclerosis and amyotrophic lateral sclerosis [J.
Luber-Narod et al, poster C.I.N.P. XVIIIth Congress, 28 Jun.-2 Jul.
1992], and in disorders of bladder function such as bladder
detrusor hyper-reflexia (Lancet, 16 May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in
the following disorders: depression, dysthymic disorders, chronic
obstructive airways disease, hypersensitivity disorders such as
poison ivy, vasospastic diseases such as angina and Reynauld's
disease, fibrosing and collagen diseases such as scleroderma and
eosinophilic fascioliasis, reflex sympathetic dystrophy such as
shoulder/hand syndrome, addiction disorders such as alcoholism,
stress related somatic disorders, neuropathy, neuralgia, disorders
related to immune enhancement or suppression such as systemic lupus
erythmatosus (European patent specification no. 0 436 334),
ophthalmic disease such as conjuctivitis, vernal conjunctivitis,
and the like, and cutaneous diseases such as contact dermatitis,
atopic dermatitis, urticaria, and other eczematoid dermatitis
(European patent specification no. 0 394 989).
In view of their metabolic instability, peptide derivatives are
likely to be of limited utility as therapeutic agents. It is for
this reason that non-peptide tachykinin antagonists are sought.
In essence, this invention provides a class of potent non-peptide
tachykinin antagonists.
The present invention provides a compound of formula (I), or a
pharmaceutically acceptable salt thereof: ##STR2## wherein m is
zero, 1 or 2;
n is zero or 1, with the proviso that the sum total of m+n is 1 or
2;
R.sup.1 represents unsubstituted phenyl or phenyl substituted by 1,
2 or 3 groups selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4 alkyl, --O(CH.sub.2).sub.p O-- where p is 1 or
2, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl,
OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b,
NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, COR.sup.a, CO.sub.2
R.sup.a or CONR.sup.a R.sup.b, where R.sup.a and R.sup.b each
independently represent hydrogen, C.sub.1-6 alkyl, phenyl or
trifluoromethyl; naphthyl; benzhydryl; or benzyl, where the
naphthyl group or each phenyl moiety of benzyl and benzhydryl may
be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or
trifluoromethyl;
R.sup.2 represents hydrogen; unsubstituted phenyl or phenyl
substituted by 1, 2 or 3 groups selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4 alkyl, --O(CH.sub.2).sub.p O-- where
p is 1 or 2, halogen, cyano, nitro, trifluoromethyl,
trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a,
NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b,
COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b, where R.sup.a
and R.sup.b are as previously defined; heteroaryl selected from
indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and
quinolinyl; naphthyl; benzhydryl; or benzyl; wherein each
heteroaryl, the naphthyl group and each phenyl moiety of benzyl and
benzhydryl may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
halogen or trifluoromethyl;
R.sup.3 and R.sup.4 each independently represents hydrogen or
C.sub.1-6 alkyl or R.sup.3 and R.sup.4 together are linked so as to
form a C.sub.1-3 alkylene chain;
Q represents CR.sup.5 R.sup.6 or NR.sup.5 ;
X and Y each independently represents hydrogen, or together form a
group .dbd.O;
Z represents a bond, O, S, SO, SO.sub.2, NR.sup.c or --(CR.sup.c
R.sup.d)--, where R.sup.c and R.sup.d each independently represent
hydrogen or C.sub.1-6 alkyl;
R.sup.5 represents C.sub.1-3 alkyl substituted by a group selected
from OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a
R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, NR.sup.a
SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a
R.sup.b, where R.sup.a and R.sup.b are as previously defined;
unsubstituted phenyl; phenyl substituted by 1, 2 or 3 groups
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl,
--O(CH.sub.2).sub.p O-- where p is 1 or 2, halogen, cyano, nitro,
trifluoromethyl, trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a,
SO.sub.2 R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a
CO.sub.2 R.sup.b, NR.sup.a SO.sub.2 R.sup.b, COR.sup.a,
CO.sub.2.sup.a, CONR.sup.a R.sup.b, or C.sub.1-3 alkyl substituted
by a group selected from OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2
R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2
R.sup.b, NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or
CONR.sup.a R.sup.b, where R.sup.a and R.sup.b are as previously
defined; benzimidazol-1-yl; 2-keto-benzimidazol-1-yl; or heteroaryl
selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl,
wherein each heteroaryl may be substituted by C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, halogen or trifluoromethyl;
R.sup.6 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4 alkyl, halogen, cyano, nitro, trifluoromethyl,
trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a,
NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b,
NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a, CONR.sup.a
R.sup.b, or C.sub.1-3 alkyl substituted by a group selected from
OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b,
NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, NR.sup.a SO.sub.2
R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b, where
R.sup.a and R.sup.b are as previously defined;
or R.sup.5 and R.sup.6 together are linked so as to form a 5- or
6-membered ring optionally substituted by .dbd.O, .dbd.S or a
C.sub.1-4 alkyl or hydroxy group, and optionally containing a
double bond, which ring may optionally contain in the ring one or
two heteroatoms selected from O and S, or groups selected from
NR.sup.c, SO or SO.sub.2, where R.sup.c is as previously defined,
and to which ring there is fused a benzene or thiophene ring, which
benzene or thiophene ring is optionally substituted by 1, 2 or 3
substituents selected from C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenylC.sub.1-4 alkyl,
trifluoromethyl, cyano, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2
R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2
R.sup.b, NR.sup.a SO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or
CONR.sup.a R.sup.b, wherein the phenyl moiety of a phenylC.sub.1-4
alkyl group may be substituted by C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen or trifluoromethyl, and R.sup.a and R.sup.b are as
previously defined.
As used herein, the definition of each expression, when it occurs
more than once in any structure, is intended to be independent of
its definition elsewhere in the same structure.
The alkyl, alkenyl and alkynyl groups referred to with respect to
the formulae herein may represent straight or branched groups.
Thus, for example, suitable alkyl groups include methyl, ethyl, n-
or iso-propyl and n-, sec-, iso- or tert-butyl. The cycloalkyl
groups referred to above may be, for example, cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. Similarly, suitable
cycloalkylalkyl groups include cyclopropylmethyl. Suitable alkenyl
groups include vinyl and allyl; and suitable alkynyl groups include
propargyl.
The term "halogen" as used herein includes fluorine, chlorine,
bromine and iodine, especially chlorine and fluorine.
The present invention includes within its scope prodrugs of the
compounds of formula (I) above. In general, such prodrugs will be
functional derivatives of the compounds of formula (I) which are
readily convertible in vivo into the required compound of formula
(I). Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in "Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Those compounds according to the invention which contain one or
more chiral centres may exist both as enantiomers and as
diastereomers. It is to be understood that all such isomers and
mixtures thereof are encompassed within the scope of the present
invention.
Preferably m is 1 or 2, n is zero or 1 and the sum total of m+n is
2. Most especially, m is 1 and n is 1.
Preferably R.sup.1 represents unsubstituted phenyl or phenyl
substituted by one or two groups selected from C.sub.1-6 alkyl such
as methyl, halogen such as chlorine, fluorine and bromine, and
trifluoromethyl. Particularly preferred substituents are chlorine
and trifluoromethyl.
Most preferably, R.sup.1 represents disubstituted phenyl, in
particular 3,4-disubstituted phenyl, especially
3,4-dichlorophenyl.
Suitable values for the group R.sup.2 include unsubstituted or
substituted phenyl, 5-membered heteroaryl such as thienyl or
furanyl, 6-membered heteroaryl such as pyridyl, quinolinyl,
naphthyl, and benzhydryl.
Preferably R.sup.2 represents unsubstituted or substituted phenyl,
especially unsubstituted phenyl.
When R.sup.2 represents substituted phenyl it preferably represents
dichlorophenyl, especially 3,4-dichlorophenyl.
Preferably R.sup.3 and R.sup.4 each independently represent
hydrogen.
Preferably R.sup.5 is C.sub.1-3 alkyl, especially --CH.sub.2 --,
substituted by a group selected from NR.sup.a COR.sup.b, NR.sup.a
SO.sub.2 R.sup.b or CO.sub.2 R.sup.a, where R.sup.a and R.sup.b are
as previously defined; unsubstituted phenyl; phenyl substituted by
a group selected from C.sub.1-6 alkyl, halogen, cyano, nitro,
OR.sup.a, NR.sup.a R.sup.b, NR.sup.a SO.sub.2 R.sup.b or C.sub.1-3
alkyl, especially --CH.sub.2 --, substituted by NR.sup.a R.sup.b,
NR.sup.a COR.sup.b or NR.sup.a SO.sub.2 R.sup.b, where R.sup.a and
R.sup.b are as previously defined; 2-keto-benzimidazol-1-yl;
pyridinyl, especially pyridin-2-yl; and pyrimidinyl, especially
pyrimidin-2-yl.
Preferably R.sup.6 is hydrogen, cyano, NR.sup.a COR.sup.b, CO.sub.2
R.sup.b or C.sub.1-3 alkyl, especially --CH.sub.2 --, substituted
by OR.sup.a, NR.sup.a COR.sup.b or NRSO.sub.2 R.sup.b, where
R.sup.a and R.sup.b are as previously defined.
Where R.sup.5 and R.sup.6 are taken together there is preferably
formed a 5- or 6-membered ring optionally substituted by .dbd.O or
a hydroxy group, and optionally containing a double bond, which
ring optionally contains in the ring an oxygen or sulfur atom or 1
or 2 NH groups, and to which ring is fused a benzene or thiophene
ring, which benzene ring is optionally substituted by OR.sup.a,
where R.sup.a is as previously defined.
As used herein, OR.sup.a is preferably OH or OCH.sub.3 ; NR.sup.a
R.sup.b is preferably NH.sub.2, NHCH.sub.3 N(CH.sub.3).sub.2 ;
NR.sup.a COR.sup.b is preferably NHCOCH.sub.3,
N(CH.sub.3)COCH.sub.3 N(Ph)COCH.sub.3 ; NR.sup.a SO.sub.2 R.sup.b
is preferably NHSO.sub.2 CH.sub.3, N(CH.sub.3)SO.sub.2 CH.sub.3 or
N(Ph)SO.sub.2 CH.sub.3 ; and CO.sub.2 R.sup.a is preferably
CO.sub.2 CH.sub.3 or CO.sub.2 CH.sub.2 CH.sub.3.
A preferred class of compounds of formula (I) is that wherein Q is
CR.sup.5 R.sup.6, wherein the group CR.sup.5 R.sup.6 is selected
from: ##STR3##
Another preferred class of compounds of formula (I) is that wherein
Q is NR.sup.5, wherein the group NR.sup.5 is selected from:
##STR4##
Particularly preferred are those compounds wherein Q represents:
##STR5##
Preferably X and Y are both hydrogen atoms.
Preferably Z is an oxygen atom.
A particular sub-class of compounds according to the invention is
represented by compounds of formula (Ia), and pharmaceutically
acceptable salts thereof. ##STR6## wherein m, n, Q, X and Y are as
defined for formula (I);
Z' is O, S or --CH.sub.2 --, especially O or S;
R.sup.20 and R.sup.21 independently represent hydrogen, C.sub.1-6
alkyl, halogen, trifluoromethyl, OR.sup.a, or NR.sup.a R.sup.b,
where R.sup.a and R.sup.b are as previously defined; and
R.sup.22 and R.sup.23 independently represent hydrogen or halogen,
preferably hydrogen or chlorine.
Particular values of R.sup.20 and R.sup.21 include hydrogen,
chlorine, fluorine, methyl, trifluoromethyl, methoxy and
dimethylamino.
Another preferred sub-class of compounds according to the invention
is represented by compounds of formula (Ib), and pharmaceutically
acceptable salts thereof: ##STR7## wherein m, n, Q, X and Y are as
defined for formula (I);
Z" is O or --CH.sub.2 --, especially O;
R.sup.24 and R.sup.25 independently represent hydrogen or chlorine;
and
R.sup.26 and R.sup.27 independently represent hydrogen or chlorine;
with the proviso that at least one of R.sup.26 and R.sup.27
represents chlorine.
Specific compounds within the scope of the present invention
include:
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-keto-1-benzim
idazolinyl)piperidine;
(S)-1'-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]spiro[1H-indene-1,
4'-piperidine];
(S)-N-({1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide;
(S)-1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-(methanesulfonam
idomethyl)-4-phenylpiperidine;
(S)-1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperidine
;
(S)-N-{1-[3-benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperid
in-4-yl}acetamide;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methoxyphenyl
)piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-pyridyl)piper
azine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-chlorophenyl)
piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-cyano-4-phenylpi
peridine;
(S)-methyl
1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperidine-4-
carboxylate;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methylphenyl)
piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-nitrophenyl)p
iperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(pyrimidin-2-yl)
piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methoxyphenyl
)piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(methanesulfo
namido)phenyl]piperidine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-{2-[N-(methyl)me
thanesulfonamido]phenyl}piperidine;
(S)-1-[-2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(methanesulfona
midomethyl)-4-phenylpiperidine;
(S)-1-[-2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(N-phenylmethan
esulfonamidomethyl)piperidine;
(S)-N-({1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide;
(S)-N-({1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperidin-4-yl}
methyl)-N-phenylacetamide;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
2'(1'H)-quinazolin]-4'(3'H)-one];
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-2,3-dihydrospiro[
1H-indene-1,4'-piperidine];
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-cyanophenyl)p
iperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methanesulfon
amidophenyl)piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
6'-[6'H]thieno[2,3-b]thiopyran]-4'(5'H)-one];
(2S,
3'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-spiro[2H-1H-be
nzopyran-2,3'-piperidine]-4-(3H)-one;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-6-methoxyspiro[2H
-1-benzopyran-2,4'-piperidine]-4-(3H)-one;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methylphenyl)
piperidine;
(S)-ethyl
2-{4-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperazin-1-yl}etha
noate;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(methanesulfo
namidomethyl)phenyl]piperazine;
(S)-N-(2-{4-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperazin-1-y
l}phenylmethyl)acetamide;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(dimethylamin
omethyl)phenyl]piperazine;
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-hydroxymethyl-4-
phenylpiperidine;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidin]-4-(3H)-one;
(2S,
4'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-3,4-dihydrospi
ro[2H-1-benzopyran-2,4'-piperidine]-4-ol;
(S)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidine];
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-aminophenyl)p
iperazine;
and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of formula (I) will
be pharmaceutically acceptable salts. Other salts may, however, be
useful in the preparation of the compounds according to the
invention (such as the dibenzoyltartrate salts) or of their
pharmaceutically acceptable salts. Suitable pharmaceutically
acceptable salts of the compounds of this invention include acid
addition salts which may, for example, be formed by mixing a
solution of the compound according to the invention with a solution
of a pharmaceutically acceptable non-toxic acid such as
hydrochloric acid, sulphuric acid, fumaric acid, maleic acid,
succinic acid, acetic acid, citric acid, tartaric acid, carbonic
acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine
groups may also comprise quaternary ammonium salts in which the
amino nitrogen atom carries a suitable organic group such as an
alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the
compounds of the invention carry an acidic moiety, suitable
pharmaceutically acceptable salts thereof may include metal salts
such as alkali metal salts, e.g. sodium or potassium salts; and
alkaline earth metal salts, e.g. calcium or magnesium salts.
Preferred salts of the compounds according to the invention include
the hydrochloride and p-toluenesulphonic acid salts.
The invention also provides pharmaceutical compositions comprising
one or more compounds of this invention in association with a
pharmaceutically acceptable carrier. Preferably these compositions
are in unit dosage forms such as tablets, pills, capsules, powders,
granules, solutions or suspensions, or suppositories, for oral,
parenteral or rectal administration, or topical administration
including administration by inhalation or insufflation.
The invention further provides a process for the preparation of a
pharmaceutical composition comprising a compound of formula (I), or
a salt or prodrug thereof, and a pharmaceutically acceptable
carrier, which process comprises bringing a compound of formula
(I), or a salt or prodrug thereof into association with a
pharmaceutically acceptable carrier.
For preparing solid compositions such as tablets, the principal
active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
non-toxic pharmaceutically acceptable salt thereof. When referring
to these preformulation compositions as homogeneous, it is meant
that the active ingredient is dispersed evenly throughout the
composition so that the composition may be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation composition is then subdivided
into unit dosage forms of the type described above containing from
0.1 to about 500 mg of the active ingredient of the present
invention. The tablets or pills of the novel composition can be
coated or otherwise compounded to provide a dosage form affording
the advantage of prolonged action. For example, the tablet or pill
can comprise an inner dosage and an outer dosage component, the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac,
cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by
injection include aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include
those comprising a compound of formula (I), as the active
ingredient, in association with a surface-active agent (or wetting
agent or surfactant) or in the form of an emulsion (as a
water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic
agents, such as polyoxyethylenesorbitans (e.g. Tween.TM. 20, 40,
60, 80 or 85) and other sorbitans (e.g. Span.TM. 20, 40, 60, 80 or
85). Compositions with a surface-active agent will conveniently
comprise between 0.05 and 5% surface-active agent, and preferably
between 0.1 and 2.5%. It will be appreciated that other ingredients
may be added, for example mannitol or other pharmaceutically
acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat
emulsions, such as Intralipid.TM., Liposyn.TM., Infonutrol.TM.,
Lipofundin.TM. and Lipiphysan.TM.. The active ingredient may be
either dissolved in a pre-mixed emulsion composition or
alternatively it may be dissolved in an oil (e.g. soybean oil,
safflower oil, cottonseed oil, sesame oil, corn oil or almond oil)
and an emulsion formed upon mixing with a phospholipid (e.g. egg
phospholipids, soybean phospholipids or soybean lecithin) and
water. It will be appreciated that other ingredients may be added,
for example glycerol or glucose, to adjust the tonicity of the
emulsion. Suitable emulsions will typically contain up to 20% oil,
for example, between 5 and 20%. The fat emulsion will preferably
comprise fat droplets between 0.1 and 1.0 .mu.m, particularly 0.1
and 0.5 .mu.m, and have a pH in range of 5.5 to 8.0.
Particularly preferred emulsion compositions are those prepared by
mixing a compound of formula (I) with Intralipid.TM. or the
components thereof (soybean oil, egg phospholipids, glycerol and
water).
Composition for inhalation or insufflation include solutions and
suspensions in pharmaceutically acceptable, aqueous or organic
solvents, or mixtures thereof, and powders. The liquid or solid
compositions may contain suitable pharmaceutically acceptable
excipients as set out above. Preferably the compositions are
administered by the oral or nasal respiratory route for local or
systemic effect. Compositions in preferably sterile
pharmaceutically acceptable solvents may be nebulised by use of
inert gases. Nebulised solutions may be breathed directly from the
nebulising device or the nebulising device may be attached to a
face mask, tent or intermittent positive pressure breathing
machine. Solution, suspension or powder compositions may be
administered, preferably orally or nasally, from devices which
deliver the formulation in an appropriate manner.
The present invention further provides a process for the
preparation of a pharmaceutical composition comprising a compound
of formula (I), which process comprises bringing a compound of
formula (I) into association with a pharmaceutically acceptable
carrier or excipient.
The compounds of formula (I) are of value in the treatment of a
wide variety of clinical conditions which are characterised by the
presence of an excess of tachykinin, in particular substance P,
activity.
Thus, for example, an excess of tachykinin, and in particular
substance P, activity is implicated in a variety of disorders of
the central nervous system. Such disorders include mood disorders,
such as depression or more particularly depressive disorders, for
example, single episodic or recurrent major depressive disorders
and dysthymic disorders, or bipolar disorders, for example, bipolar
I disorder, bipolar II disorder and cyclothymic disorder; anxiety
disorders, such as panic disorder with or without agoraphobia,
agoraphobia without history of panic disorder, specific phobias,
for example, specific animal phobias, social phobias,
obsessive-compulsive disorder, stress disorders including
post-traumatic stress disorder and acute stress disorder, and
generalised anxiety disorders; schizophrenia and other psychotic
disorders, for example, schizophreniform disorders, schizoaffective
disorders, delusional disorders, brief psychotic disorders, shared
psychotic disorders and psychotic disorders with delusions or
hallucinations; delerium, dementia, and amnestic and other
cognitive or neurodegenerative disorders, such as Alzheimer's
disease, senile dementia, dementia of the Alzheimer's type,
vascular dementia, and other dementias, for example, due to HIV
disease, head trauma, Parkinson's disease, Huntington's disease,
Pick's disease, Creutzfeldt-Jakob disease, or due to multiple
aetiologies; Parkinson's disease and other extra-pyramidal movement
disorders such as medication-induced movement disorders, for
example, neuroleptic-induced parkinsonism, neuroleptic malignant
syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced
acute akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremour; substance-related disorders
arising from the use of alcohol, amphetamines (or amphetamine-like
substances) caffeine, cannabis, cocaine, hallucinogens, inhalants
and aerosol propellants, nicotine, opioids, phenylglycidine
derivatives, sedatives, hypnotics, and anxiolytics, which
substance-related disorders include dependence and abuse,
intoxication, withdrawal, intoxication delerium, withdrawal
delerium, persisting dementia, psychotic disorders, mood disorders,
anxiety disorders, sexual dysfunction and sleep disorders;
epilepsy; Down's syndrome; demyelinating diseases such as MS and
ALS and other neuropathological disorders such as peripheral
neuropathy, for example diabetic and chemotherapy-induced
neuropathy, and postherpetic neuralgia, trigeminal neuralgia,
segmental or intercostal neuralgia and other neuralgias; and
cerebral vascular disorders due to acute or chronic cerebrovascular
damage such as cerebral infarction, subarachnoid haemorrhage or
cerebral oedema.
Tachykinin, and in particular substance P, activity is also
involved in nociception and pain. The compounds of the present
invention will therefore be of use in the prevention or treatment
of diseases and conditions in which pain predominates, including
soft tissue and peripheral damage, such as acute trauma,
osteoarthritis, rheumatoid arthritis, musculo-skeletal pain,
particularly after trauma, spinal pain, dental pain, myofascial
pain syndromes, headache, episiotomy pain, and burns; deep and
visceral pain, such as heart pain, muscle pain, eye pain, orofacial
pain, for example, odontalgia, abdominal pain, gynaecological pain,
for example, dysmenorrhoea, and labour pain; pain associated with
nerve and root damage, such as pain associated with peripheral
nerve disorders, for example, nerve entrapment and brachial plexus
avulsions, amputation, peripheral neuropathies, tic douloureux,
atypical facial pain, nerve root damage, and arachnoiditis; pain
associated with carcinoma, often referred to as cancer pain;
central nervous system pain, such as pain due to spinal cord or
brain stem damage; low back pain; sciatica; ankylosing spondylitis,
gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be
of use in the treatment of respiratory diseases, particularly those
associated with excess mucus secretion, such as chronic obstructive
airways disease, bronchopneumonia, chronic bronchitis, cystic
fibrosis and asthma, adult respiratory distress syndrome, and
bronchospasm; inflammatory diseases such as inflammatory bowel
disease, psoriasis; fibrositis, osteoarthritis, rheumatoid
arthritis, pruritis and sunburn; allergies such as eczema and
rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic
diseases such as conjunctivitis, vernal conjunctivitis, and the
like; opththalmic conditions associated with cell proliferation
such as proliferative vitreoretinopathy; cutaneous diseases such as
contact dermatitis, atopic dermatitis, urticaria, and other
eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be
of use in the treatment of neoplasms, including breast tumours,
neuroganglioblastomas and small cell carcinomas such as small cell
lung cancer.
Tachykinin, and in particular substance P, antagonists may also be
of use in the treatment of gastrointestinal (GI) disorders,
including inflammatory disorders and diseases of the GI tract such
as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric
lymphomas, disorders associated with the neuronal control of
viscera, ulcerative colitis, Crohn's disease, irritable bowel
syndrome and emesis, including acute, delayed or anticipatory
emesis such as emesis induced by chemotherapy, radiation, toxins,
viral or bacterial infections, pregnancy, vestibular disorders, for
example, motion sickness, vertigo, dizziness and Meniere's disease,
surgery, migraine, variations in intercranial pressure,
gastro-oesophageal reflux disease, acid indigestion, over
indulgence in food and drink, acid stomach, waterbrash or
regurgitation, heartburn, for example, episodic, nocturnal or
meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be
of use in the treatment of a variety of other conditions including
stress related somatic disorders; reflex sympathetic dystrophy such
as shoulder/hand syndrome; adverse immunological reactions such as
rejection of transplanted tissues and disorders related to immune
enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy,
disorders of bladder function such as cystitis, bladder detrusor
hyper-reflexia and incontinence; fibrosing and collagen diseases
such as scleroderma and eosinophilic fascioliasis; disorders of
blood flow caused by vasodilation and vasospastic diseases such as
angina, vascular headache, migraine and Reynaud's disease; and pain
or nociception attributable to or associated with any of the
foregoing conditions, especially the transmission of pain in
migraine.
The compounds of formula (I) are also of value in the treatment of
a combination of the above conditions, in particular in the
treatment of combined post-operative pain and post-operative nausea
and vomiting.
The compounds of formula (I) are particularly useful in the
treatment of emesis, including acute, delayed or anticipatory
emesis, such as emesis induced by chemotherapy, radiation, toxins,
pregnancy, vestibular disorders, motion, surgery, migraine, and
variations in intercranial pressure. Most especially, the compounds
of formula (I) are of use in the treatment of emesis induced by
antineoplastic (cytotoxic) agents including those routinely used in
cancer chemotherapy, and emesis induced by other pharmacological
agents, for example, rolipram.
Examples of such chemotherapeutic agents include alkylating agents,
for example, nitrogen mustards, ethyleneimine compounds, alkyl
sulphonates and other compounds with an alkylating action such as
nitrosoureas, cisplatin and dacarbazine; antimetabolites, for
example, folic acid, purine or pyrimidine antagonists; mitotic
inhibitors, for example, vinca alkaloids and derivatives of
podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for
instance, by D. J. Stewart in Nausea and Vomiting: Recent Research
and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc.,
Boca Raton, Fla., U.S.A. (1991) pages 177-203, especially page 188.
Commonly used chemotherapeutic agents include cisplatin,
dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen
mustard), streptozocin, cyclophosphamide, carmustine (BCNU),
lomustine (CCNU), doxorubicin (adriamycin), daunorubicin,
procarbazine, mitomycin, cytarabine, etoposide, methotrexate,
5-fluorouracil, vinblastine, vincristine, bleomycin and
chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984)
68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of
emesis induced by radiation including radiation therapy such as in
the treatment of cancer, or radiation sickness; and in the
treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be
presented together with another therapeutic agent as a combined
preparation for simultaneous, separate or sequential use for the
relief of emesis. Such combined preparations may be, for example,
in the form of a twin pack.
A further aspect of the present invention comprises the compounds
of formula (I) in combination with a 5-HT.sub.3 antagonist, such as
ondansetron, granisetron or tropisetron, or other anti-emetic
medicaments, for example, a dopamine antagonist such as
metoclopramide or GABA.sub.B receptor agonists such as baclofen.
Additionally, a compound of formula (I) may be administered in
combination with an anti-inflammatory corticosteroid, such as
dexamethasone, triamcinolone, triamcinolone acetonide, flunisolide,
budesonide, or others such as those disclosed in U.S. Pat. Nos.
2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,
3,928,326 and 3,749,712. Dexamethasone (Decadron.TM.) is
particularly preferred. Furthermore, a compound of formula (I) may
be administered in combination with a chemotherapeutic agent such
as an alkylating agent, antimetabolite, mitotic inhibitor or
cytotoxic antibiotic, as described above. In general, the currently
available dosage forms of the known therapeutic agents for use in
such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis
described by F. D. Tattersall et al, in Eur. J. pharmacol., (1993)
250, R5-R6, the compounds of the present invention were found to
attenuate the retching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the
treatment of pain or nociception and/or inflammation and disorders
associated therewith such as, for example, neuropathy, such as
diabetic and chemotherapy-induced neuropathy, postherpetic and
other neuralgias, asthma, osteroarthritis, rheumatoid arthritis,
headache and especially migraine.
The present invention further provides a compound of formula (I)
for use in therapy.
According to a further or alternative aspect, the present invention
provides a compound of formula (I) for use in the manufacture of a
medicament for the treatment of physiological disorders associated
with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or
prevention of physiological disorders associated with an excess of
tachykinins, especially substance P, which method comprises
administration to a patient in need thereof of a tachykinin
reducing amount of a compound of formula (I) or a composition
comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to
employ a compound according to the present invention in conjunction
with another pharmacologically active agent. For example, for the
treatment of respiratory diseases such as asthma, a compound of
formula (I) may be used in conjunction with a bronchodilator, such
as a .beta..sub.2 -adrenergic receptor agonist or tachykinin
antagonist which acts at NK-2 receptors. The compound of formula
(I) and the bronchodilator may be administered to a patient
simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with
a leukotriene antagonists, such as a leukotriene D.sub.4 antagonist
such as a compound selected from those disclosed in European patent
specification nos. 0 480 717 and 0 604 114 and in U.S. Pat. No.
4,859,692 and 5,270,324. This combination is particularly useful in
the treatment of respiratory diseases such as asthma, chronic
bronchitis and cough.
The present invention accordingly provides a method for the
treatment of a respiratory disease, such as asthma, which method
comprises administration to a patient in need thereof of an
effective amount of a compound of formula (I) and an effective
amount of a bronchodilator.
The present invention also provides a composition comprising a
compound of formula (I), a bronchodilator, and a pharmaceutically
acceptable carrier.
It will be appreciated that for the treatment or prevention of
migraine, a compound of the present invention may be used in
conjunction with other anti-migraine agents, such as ergotamines or
5-HT.sub.1 agonists, especially sumatriptan, naratriptan,
zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound
of the present invention may be used in conjunction with an
antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of inflammatory conditions in the
lower urinary tract, especially cystitis, a compound of the present
invention may be used in conjunction with an antiinflammatory agent
such as a bradykinin receptor antagonist.
It will appreciated that for the treatment or prevention of pain or
nociception, a compound of the present invention may be used in
conjunction with other analgesics, such as acetaminophen
(paracetamol), aspirin and other NSAIDs and, in particular, opioid
analgesics, especially morphine. Specific anti-inflammatory agents
include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen,
piroxicam and sulindac. Suitable opioid analgesics of use in
conjunction with a compound of the present invention include
morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone,
hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine,
butorphanol, fentanyl, sufentanyl, meperidine, methadone,
nalbuphine, propoxyphene and pentazocine; or a pharmaceutically
acceptable salt thereof. Preferred salts of these opioid analgesics
include morphine sulphate, morphine hydrochloride, morphine
tartrate, codeine phosphate, codeine sulphate, dihydrocodeine
bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate,
hydromorphone hydrochloride, levorphanol tartrate, oxymorphone
hydrochloride, alfentanil hydrochloride, buprenorphine
hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine
hydrochloride, methadone hydrochloride, nalbuphine hydrochloride,
propoxyphene hydrochloride, propoxyphene napsylate
(2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocine
hydrochloride.
Therefore, in a further aspect of the present invention, there is
provided a pharmaceutical composition comprising a compound of the
present invention and an analgesic, together with at least one
pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there
is provided a product comprising a compound of the present
invention and an analgesic as a combined preparation for
simultaneous, separate or sequential use in the treatment or
prevention of pain or nociception.
It will be appreciated that for the treatment of depression or
anxiety, a compound of the present invention may be used in
conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors
(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible
inhibitors of monoamine oxidase (RIMAs), serotonin and
noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing
factor (CRF) antagonists, .alpha.-adrenoreceptor antagonists and
atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine
tricyclics and secondary amine tricyclics. Suitable examples of
tertiary amine tricyclics include: amitriptyline, clomipramine,
doxepin, imipramine and trimipramine, and pharmaceutically
acceptable salts thereof. Suitable examples of secondary amine
tricyclics include: amoxapine, desipramine, maprotiline,
nortriptyline and protriptyline, and pharmaceutically acceptable
salts thereof.
Suitable selective serotonin reuptake inhibitors include:
fluoxetine, fluvoxamine, paroxetine and sertraline, and
pharmaceutically acceptable salts thereof.
Suitable monoamine oxidase inhibitors include: isocarboxazid,
phenelzine, tranylcypromine and selegiline, and pharmaceutically
acceptable salts thereof.
Suitable reversible inhibitors of monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in
the present invention include: venlafaxine, and pharmaceutically
acceptable salts thereof.
Suitable CRF antagonists include those compounds described in
International Patent Specification Nos. WO 94/13643, WO 94/13644,
WO 94/13661, WO 94/13676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium,
nefazodone, trazodone and viloxazine, and pharmaceutically
acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and
5-HT.sub.1A agonists or antagonists, especially 5-HT.sub.1A partial
agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide,
clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam
and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HT.sub.1A receptor agonists or antagonists include, in
particular, the 5-HT.sub.1A receptor partial agonists buspirone,
flesinoxan, gepirone and ipsaperone, and pharmaceutically
acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is
provided a pharmaceutical composition comprising a compound of the
present invention and an anti-depressant or anti-anxiety agent,
together with at least one pharmaceutically acceptable carrier or
excipient.
In a further or alternative aspect of the present invention, there
is provided a product comprising a compound of the present
invention and an anti-depressant or anti-anxiety agent as a
combined preparation for simultaneous, separate or sequential use
for the treatment or prevention of depression and/or anxiety.
The excellent pharmacological profile of the compounds of the
present invention offers the opportunity for their use in therapy
at low doses thereby minimising the risk of unwanted side
effects.
In the treatment of the conditions associated with an excess of
tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per
day, in particular about 0.01 to about 25 mg/kg, such as from about
0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the
neurotransmission of pain sensations, a suitable dosage level is
about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg
per day, and especially about 0.005 to 5 mg/kg per day. The
compounds may be administered on a regimen of 1 to 4 times per day,
preferably once or twice per day.
In the treatment of emesis using an injectable formulation, a
suitable dosage level is about 0.001 to 10 mg/kg per day,
preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 1
mg/kg per day. The compounds may be administered on a regimen of 1
to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I)
required for use in any treatment will vary not only with the
particular compounds or composition selected but also with the
route of administration, the nature of the condition being treated,
and the age and condition of the patient, and will ultimately by at
the discretion of the attendant physician.
According to process (A), compounds of formula (I) wherein X and Y
are both hydrogen, may be prepared from compounds of formula (II):
##STR8## wherein R, R.sup.1, R.sup.3, R.sup.4, R.sup.5, Q, Z, m and
n are as defined for formula (I), by reaction with an aldehyde of
formula R.sup.2 --CHO in the presence of a reducing agent.
Suitable reducing agent of use in the reaction include hydride
reducing agent such as sodium cyanoborohydride or sodium
borohydride.
The reaction is conveniently effected in a suitable solvent such as
dimethylformamide or dichloromethane, conveniently at room
temperature.
According to a process (B), compounds of formula (I) wherein X and
Y together form a group .dbd.O, may be prepared by the reaction of
a compound of formula (II) with an acyl halide of formula R.sup.2
--COHal where Hal is a halogen atom, typically chlorine, fluorine
or bromine, especially chlorine.
The reaction is conveniently effected in the presence of an
acylation catalyst such as 4-dimethylaminopyridine in a suitable
solvent such as dichloromethane at a temperature between
-10.degree. C. and 40.degree. C., conveniently at room
temperature.
According to a further process (C), compounds of formula (I) may be
prepared by the reaction of a compound of formula (III) with a
compound of formula (IV): ##STR9## wherein R, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, Q, X, Y, Z, m and n are as defined for
formula (I).
The reaction is effected in the presence of a suitable coupling
agent, such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(BOP-Cl), dicyclocarbonyldiimide, N,N'-carbonyldiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide optionally in the
presence of an additive such as 1-hydroxybenzotriazole.
The choice of solvent for the reaction will depend upon the
coupling reagent used thus, for example, with BOP-Cl a suitable
solvent is a halogenated hydrocarbon, especially
dichloromethane.
Further useful synthetic methods are those commonly used in
standard synthesis of amino acids, for example, as described in
Chemistry and Biochemistry of the Amino Acids, Ed. G. C. Barrett,
Chapman and Hall, London 1985.
According to a further process (D), compounds of formula (I) may be
prepared by the interconversion of another compound of formula
(I).
Interconversion reactions will be readily apparent to a person
skilled in the art. Thus, for example, a functional group such as
cyano may be modified by reduction, for instance, by catalytic
hydrogenation in the presence of a noble metal catalyst or an oxide
thereof, e.g. platinum oxide, to give a corresponding compound of
formula (I) where the CN group is replaced by --CH.sub.2 NH.sub.2.
This in turn may be modified by reaction with, for example,
methanesulfonyl chloride to give a --CH.sub.2 NHSO.sub.2 CH.sub.3
group, or by reaction with acetic anhydride to give a --CH.sub.2
NHCOCH.sub.3 group.
A carboxylic acid moiety may be esterified in a conventional
manner, for example using sulfuric acid and methanol to give the
corresponding methyl ester. Compounds where R.sup.5 represents
--CH.sub.2 N(Ph)SO.sub.2 CH.sub.3 and --CH.sub.2 N(Ph)COCH.sub.3
may also be prepared from the corresponding compound where R.sup.5
is a --CO.sub.2 H, by reaction with aniline in the presence of
BOP-Cl followed by reduction with borane to give an intermediate
where R.sup.5 is a --CH.sub.2 NH(Ph) group which may then be
reacted with methanesulfonyl chloride or acetic anhydride to give
the desired products.
A nitro group may also be converted to the corresponding
sulfonamide by reaction with tin(II) chloride (to give the
corresponding primary amine) followed by reaction with
methanesulfonyl chloride.
Compounds of formula (II) may be prepared from a suitably protected
compound of formula (V): ##STR10## wherein R.sup.1, R.sup.3,
R.sup.4, and Z are as defined for formula (I) and R.sup.30 is an
amine protecting group, for example, tert-butoxycarbonyl (t-BOC),
by reaction with a compound of formula (IV) using the conditions of
process (C), followed by deprotection in a conventional manner, for
instance using hydrogen chloride in methanol.
Compounds of formula (III) may be prepared from a deprotected
derivative corresponding to a compound of formula (V) by reaction
with an aldehyde of formula R.sup.2 --CHO under the conditions of
process (A) or an acyl halide of formula R.sup.2 --COHal under the
conditions of process (B).
Compounds of formula (V) may be prepared by reaction of a compound
of formula (VI): ##STR11## wherein R.sup.3, R.sup.4, and Z are as
defined for formula (I) and R.sup.30 is a protecting group as
defined above, by reaction with compound of the formula R.sup.1
--CH.sub.2 L, where L is a leaving group, for example, a halogen
atom such as chlorine, bromine or iodine, or an alkyl- or
arylsulphonyloxy group such as a mesylate or tosylate group. The
reaction is effected in the presence of a suitable base, for
example, an alkali metal hydride such as sodium hydride.
Compounds of formula (VI) are commercially available or may be
prepared by known procedures from available starting materials, for
example, using methods described for process (D).
Compounds of formula (VI) where Q is CR.sup.5 R.sup.6 in which
R.sup.5 is a phenyl moiety and R.sup.6 is hydrogen, may be prepared
from a corresponding ketone. Thus, for instance, where m and n are
both 1, 1-tert-butoxycarbonylpiperidin-4-one may be converted to
the corresponding enol triflate by reaction with lithium
diisopropylamide followed by addition of
N-phenylbis(trifluoromethanesulfonimide), which in turn may then be
coupled to a phenylboronic acid derivative in the presence of a
suitable catalyst, for example,
tetrakis(triphenylphosphine)palladium(0), followed by hydrogenation
in the presence of, for example, palladium on carbon.
Where the above-described processes for the preparation of the
compounds according to the invention give rise to mixtures of
stereoisomers these isomers may, if desired, be separated, suitably
by conventional techniques such as preparative chromatography.
The novel compounds which contain one or more chiral centres may be
prepared in racemic form, or individual enantiomers may be prepared
either by enantiospecific synthesis or by resolution.
During any of the above synthetic sequences it may be necessary
and/or desirable to protect sensitive or reactive groups on any of
the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum
Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, John Wiley & Sons, 1991. The protecting
groups may be removed at a convenient subsequent stage using
methods known from the art.
The exemplified compounds of the invention were tested by the
methods set out at pages 82 to 85 of International Patent
Specification No. WO 93/04040. The compounds were found to be
active with IC.sub.50 at the NK.sub.1 receptor of less than 1
.mu.M.
The compounds of this invention may be formulated as specifically
illustrated at pages 81 to 82 of International Patent Specification
No. 93/04040.
The following Examples illustrate the preparation of compounds
according to the invention.
INTERMEDIATE 1
N-[(4-Phenylpiperidin-4-yl)methyl]methanesulfonamide
Hydrochloride
a) 4-Aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine
Di-t-butyldicarbonate (13.10 g, 60 mmol) in 1,4-dioxane (50 mL) was
added to a stirred mixture of 4-cyano-4-phenylpiperidine
hydrochloride (11.14 g, 50 mmol) and sodium carbonate (13.25 g, 125
mmol) in water (150 mL) and the mixture was stirred at room
temperature for 6 h. Water (150 mL) was added and the mixture was
extracted with ethyl acetate (3.times.150 mL). The combined organic
fractions were washed with aqueous citric acid (10%, 2.times.100
mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and
brine (100 mL), dried (MgSO.sub.4) and the solvent was evaporated
under reduced pressure. The residue was dissolved in ethanol-acetic
acid (95:5, 200 mL), platinum oxide (1 g) was added and the mixture
was shaken under hydrogen (50 psi) for 22 h., adding further
platinum oxide (1 g) after 4 h. The mixture was filtered through
Hyflo, further ethanol (85 mL), acetic acid (15 mL) and platinum
oxide (1 g) were added and the mixture was shaken under hydrogen
(50 psi) for 46 h., adding further platinum oxide (1 g) after 22 h.
The mixture was filtered through Hyflo and the solvent was
evaporated under reduced pressure. Aqueous ammonia (saturated, 200
mL) was added and the mixture was extracted with ethyl acetate
(3.times.200 mL). The combined organic fractions were dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure
to give the crude title compound as an orange oil (15.92 g),
.delta..sub.H (250 MHz, CDCl.sub.3) 7.41-7.21 (5H, m), 3.74 (2H,
m), 3.05 (2H, m), 2.75 (2H, s), 2.19 (2H, m), 1.80 (2H, br s), 1.69
(2H, m), and 1.43 (9H, s).
b)
N-[(1-t-Butoxycarbonyl-4-phenylpiperidin-4-yl)methyl]methanesulfonamide
Methanesulfonyl chloride (2.32 mL, 3.44 g, 33 mmol) was added
dropwise to a stirred, cooled (0.degree. C.) solution of crude
4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and
pyridine (3.64 mL, 3.56 g, 45 mmol) in dichloromethane (100 mL) and
the mixture was stirred at room temperature for 18 h. The solvent
was evaporated under reduced pressure, aqueous sodium hydrogen
carbonate (saturated, 100 mL) was added and the mixture was
extracted with ethyl acetate (3.times.100 mL). The combined organic
fractions were washed with aqueous citric acid (10%, 2.times.100
mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and
brine (100 mL), dried (MgSO.sub.4) and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with ethyl acetate/hexane
(30:70 increasing to 80:20) to give the title compound as a
colorless solid (5.65 g, 61% from 4-cyano-4-phenylpiperidine
hydrochloride), .delta..sub.H (250 MHz, CDCl.sub.3) 7.46-7.26 (5H,
m), 3.88 (1H, br t, J 6.7 Hz), 3.72 (2H, m), 3.23 (2H, br d, J 6.7
Hz), 3.13 (2H, m), 2.71 (3H, s), 2.21 (2H, m), 1.78 (2H, m), and
1.44 (9H, s).
c) N-[(4-Phenylpiperidin-4-yl)methyl]methanesulfonamide
Hydrochloride
Methanolic hydrogen chloride (4M, 40 mL) was added to a stirred,
cooled (0.degree. C.) suspension of
N-[(1-t-butoxycarbonyl-4-phenylpiperidin-4-yl)methyl]methanesulfonamide
(5.65 g, 15.4 mmol) in methanol (20 mL) and the mixture was stirred
at room temperature for 20 h. The solvent was evaporated under
reduced pressure to give the title compound as a tan solid (4.66 g,
100%), .delta..sub.H (250 MHz, d.sub.6 -DMSO) 9.05 (1H, br s), 8.86
(1H, br s), 7.41-7.26 (5H, m), 6.95 (1H, t, J 6.9 Hz), 3.18 (2H,
m), 3.05 (2H, d, J 6.9 Hz), 2.70 (2H, m), 2.64 (3H, s), 2.26 (2H,
m), and 2.02 (2H, m).
INTERMEDIATE 2
N-[(4-Phenylpiperidin-4-yl)methyl]acetamide Hydrochloride
a)
N-[(1-t-Butoxycarbonyl-4-phenylpiperidin-4-yl)methyl]acetamide
Acetic anhydride (2.59 mL, 2.81 g, 27.5 mmol) was added dropwise to
a stirred, cooled (0.degree. C.) solution of
4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and
pyridine (3.03 mL, 2.97 g, 37.5 mmol) in dichloromethane (100 mL)
and the mixture was stirred at room temperature for 18 h. The
solvent was evaporated under reduced pressure, aqueous sodium
hydrogen carbonate (saturated, 100 mL) was added and the mixture
was extracted with ethyl acetate (3.times.100 mL). The combined
organic fractions were washed with aqueous citric acid (10%,
2.times.100 mL), aqueous sodium hydrogen carbonate (saturated, 100
mL) and brine (100 mL), dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with ethyl
acetate/hexane (50:50 increasing to 100:0) to give the title
compound as an off-white solid (5.96 g, 72% from
4-cyano-4-phenylpiperidine hydrochloride), .delta..sub.H (250 MHz,
CDCl.sub.3) 7.45-7.26 (5H, m), 5.00 (1H, br m), 3.67 (2H, m), 3.45
(2H, br m), 3.21 (2H, m), 2.08 (2H, m), 1.88 (3H, s), 1.78 (2H, m),
and 1.43 (9H, s).
b) N-[(4-Phenylpiperidin-4-yl)methyl]acetamide Hydrochloride
Methanolic hydrogen chloride (4M, 40 mL) was added to a stirred,
cooled (0.degree. C.) suspension of
N-[(1-t-butoxycarbonyl-4-phenylpiperidin-4-yl)methyl]methanesulfonamide
(5.90 g, 17.8 mmol) in methanol (40 mL) and the mixture was stirred
at room temperature for 20 h. The solvent was evaporated under
reduced pressure to give the title compound as a tan foam (4.67 g,
98%), .delta..sub.H (250 MHz, d.sub.6 -DMSO) 9.09 (1H, br s), 8.88
(1H, br s), 7.73 (1H, t, J 6.3 Hz), 7.43-7.24 (5H, m), 3.18 (4H,
m), 2.70 (2H, m), 2.21 (2H, m), 1.97 (2H, m), and 1.76 (3H, s).
INTERMEDIATE 3
Methyl 4-Phenylpiperidine-4-carboxylate Trifluoroacetate
a) Methyl 1-t-Butoxycarbonyl-4-phenylpiperidine-4-carboxylate
A mixture of 4-phenyl-4-piperidinecarboxylic acid
4-methylbenzenesulfonate (20 g) and methanolic sulfuric acid (10%,
250 mL) was heated under reflux for 24 h., cooled to room
temperature and the solvent was evaporated under reduced pressure.
The residue was dissolved in water (100 mL) and the pH was adjusted
to 8.5 with aqueous sodium hydroxide (4M). 1,4-Dioxan (50 mL) and
di-t-butyldicarbonate (11.56 g) were added and the mixture was
stirred at room temperature for 24 h. The 1,4-dioxan was evaporated
under reduced pressure and the aqueous residue was extracted with
ethyl acetate (100 mL). The organic layer was dried (MgSO.sub.4)
and the solvent was evaporated under reduced pressure to give the
title compound as a colorless solid (16.1 g) .delta..sub.H
(CDCl.sub.3) 1.45 (9H, s), 1.85-1.91 (2H, m), 2.48-2.54 (2H, m),
3.36 (2H, m), 3.73 (3H, s), 3.84-3.95 (2H, m), and 7.22-7.38 (5H,
m).
b) Methyl 4-Phenylpiperidine-4-carboxylate Trifluoroacetate
Methyl 1-t-butoxycarbonyl-4-phenylpiperidine-4-carboxylate (5.0 g)
was dissolved in trifluoroacetic acid-dichloromethane (10%, 100 mL)
and the mixture was stirred at room temperature for 6 h. The
solvent was evaporated under reduced pressure to give the title
compound as a yellow gum (5.2 g), .delta..sub.H (CDCl.sub.3)
2.11-2.20 (2H, m), 2.64-2.68 (2H, m), 3.03-3.13 (2H, m), 3.38-3.44
(2H, m), 3.63 (3H, s), 7.18-7.33 (5H, m), and 7.98 (1H, br s).
INTERMEDIATE 4
4-(2-Methoxyphenyl)piperidine Hydrochloride
a)
1-t-Butoxycarbonyl-4-trifluoromethansulfonyloxy-1,2,3,6-tetrahydropyridine
A solution of 1-t-butoxycarbonylpiperidin-4-one (1.0 g) in
tetrahydrofuran (10 mL) was added dropwise to a stirred, cooled
(-78.degree. C.) solution of lithium diisopropylamide [freshly
prepared from diisopropylamine (555 mg) and n-butyllithium (1.6M in
hexane, 3.5 mL)] in tetrahydrofuran (40 mL) and the mixture was
stirred at -78.degree. C. for 20 min. A solution of
N-phenylbis(trifluoromethanesulfonimide) (1.96 g) in
tetrahydrofuran (10 mL) was added and the solution was allowed to
warm to room temperature and stirred for 1 h. The solvent was
evaporated under reduced pressure and the residue was partitioned
between ethyl acetate and water. The organic layer was dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure.
The residue was purified by chromatography on alumina (ICN GIII)
eluting with EtOAc/Hexane (10:90) to give the title compound as a
colorless solid (1.31 g), .delta..sub.H (CDCl.sub.3) 1.47 (9H, s),
2.44 (2H, m), 3.63 (2H, t, J 7.0 Hz), 4.04 (2H, m), and 5.76 (1H,
br s).
b) 2-Methoxyphenylboronic Acid
n-Butyllithium (1.6M in hexane, 13.0 mL) was added to a stirred,
cooled (-78.degree. C.) solution of 2-bromoanisole (3.74 g) in
tetrahydrofuran (20 mL) and the mixture was stirred at -78.degree.
C. for 20 min. Trimethylborate (5.92 g) was added and the solution
was allowed to warm to room temperature and stirred for 24 h. The
mixture was cooled to 0.degree. C. and acidified with aqueous
hydrochloric acid (5M). The mixture was extracted with
dichloromethane (4.times.50 mL) and the combined organic fractions
were dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure to give the title compound as a colorless solid
(3.2 g), .delta..sub.H (CDCl.sub.3) 3.91 (3H, s), 6.09 (2H, s), and
6.87-7.03 (4H, m).
c) 4-(2-Methoxyphenyl)piperidine Hydrochloride
Tetrakis(triphenylphosphine)palladium (0) (100 mg) was added to a
degassed mixture of
1-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridin
e (810 mg), 2-methoxyphenylboronic acid (519 mg), lithium chloride
(405 mg) and aqueous sodium carbonate (2N, 3.5 mL) in
1,2-dimethoxyethane (20 mL). The resulting solution was heated
under reflux for 3 h., cooled to room temperature and the solvent
was evaporated under reduced pressure. The residue was partitioned
between ethyl acetate and aqueous sodium carbonate (2M) and the
organic layer was separated, dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was dissolved in
ethanol, palladium on carbon (10%) was added and the mixture was
shaken under hydrogen (50 psi.) for 3 h. The mixture was filtered
through Hyflo and the solvent was evaporated under reduced
pressure. The residue was purified by MPLC on silica gel, eluting
with EtOAc/Hexane (5:95) and the residue was deprotected with
ethanolic hydrogen chloride to give the title compound as a
colorless solid (340 mg), .delta..sub.H (d.sub.6 -DMSO), 1.54-1.59
(2H, m), 1.77-1.81 (2H, m), 2.77 (2H, td, J 11.0, 1.0 Hz), 3.07
(1H, td, J 11.0, 1.0 Hz), 3.11 (2H, br m), 3.82 (3H, s), 6.85 (1H,
d, J 6.0 Hz), 6.93 (1H, t, J 6.0 Hz), 7.15-7.21 (2H, m).
INTERMEDIATE 5
N-[2-(Piperidin-4-yl)phenyl]methanesulfonamide Trifluoroacetate
a) t-Butyl
(1-t-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbamate
Tetrakis(triphenylphosphine)palladium (0) (100 mg) was added to a
degassed mixture of
1-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridin
e (5.0 g), 2-(t-butoxycarbonylamino)phenylboronic acid (Tetrahedron
Lett. 1993, 28, 5093) (4.99 g), lithium chloride (1.94 g) and
aqueous sodium carbonate (2N, 21 mL) in 1,2-dimethoxyethane (100
mL). The resulting solution was heated under reflux for 3 h.,
cooled to room temperature and the solvent was evaporated under
reduced pressure. The residue was partitioned between ethyl acetate
and aqueous sodium carbonate (2M) and the organic layer was
separated, dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by MPLC on silica gel,
eluting with EtOAc/Hexane (5:95) to give the title compound as a
waxy solid (2.7 g), .delta..sub.H (CDCl.sub.3) 1.43 (18H, s), 2.29
(2H, m), 3.57 (2H, t, J 8.0 Hz), 4.00 (2H, m), 5.64 (1H, br s),
6.46 (1H, br s), 6.92-6.96 (2H, m), 7.15-7.19 (1H, m), 7.87 (1H,
m).
b) t-Butyl (1-t-Butoxycarbonylpiperidin-4-yl)phenylcarbamate
t-Butyl
(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbamate
(2.5 g) was dissolved in ethanol, palladium on carbon (10%) was
added and the mixture was shaken under hydrogen (50 psi.) for 3 h.
The mixture was filtered through Hyflo and the solvent was
evaporated under reduced pressure. The residue was purified by MPLC
on silica gel, eluting with EtOAc/Hexane (5:95) to give the title
compound as a clear oil (2.44 g), .delta..sub.H (CDCl.sub.3) 1.51
(9H, s), 1.55 (9H, s), 1.69 (2H, m), 1.79 (2H, m), 2.77 (3H, m),
4.24 (2H, m), 6.18 (1H, br s), 7.12-7.18 (3H, m), 7.52 (1H, m). m/e
(CI.sup.+) 377 (MH.sup.+).
c) 1-t-Butoxycarbonyl-4-(2-aminophenyl)piperidine
t-Butyl (1-t-butoxycarbonylpiperidin-4-yl)phenylcarbamate (290 mg)
was dissolved in trifluoroacetic acid-dichloromethane (10%, 20 mL)
and stirred at room temperature for 2 h. The solvent was evaporated
under reduced pressure and the residue was partitioned between
aqueous sodium hydroxide (2M) and ether (30 mL). The organic layer
was separated, dried (MgSO.sub.4) and the solvent was evaporated
under reduced pressure. The residue was dissolved in
dichloromethane (20 mL) and cooled in ice. Di-t-butyldicarbonate
(161 mg) was added and the mixture was stirred at room temperature
for 30 min. The solvent was evaporated under reduced pressure and
the residue was purified by MPLC on silica gel, eluting with
EtOAc/Hexane (5:95) to give the title compound as a clear oil (141
mg), .delta..sub.H (CDCl.sub.3) 1.55 (9H, s), 1.59 (2H, m), 1.82
(2H, m), 2.58 (1H, m), 2.77 (1H, m), 3.64 (2H, br s), 4.16 (2H, m),
6.68-6.79 (2H, m), 7.01-7.26 (2H, m).
d)
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide
Methanesulfonyl chloride (364 mg) was added to a solution of
1-t-butoxycarbonyl-4-(2-aminophenyl)piperidine (880 mg) and
pyridine (252 mg) in dichloromethane. The mixture was heated under
reflux for 30 min., cooled to room temperature and the solvent was
evaporated under reduced pressure. The residue was partitioned
between aqueous citric acid (10%) and ethyl acetate (100 mL). The
organic layer was separated, dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure to give the title compound as a
yellow solid (1.15 g), .delta..sub.H (CDCl.sub.3) 1.48 (9H, s),
1.60 (2H, m), 1.73 (2H, m), 2.83 (2H, m), 3.04 (3H, s), 3.09 (1H,
m), 4.26 (2H, m), 6.21 (1H, br s), 7.21-7.37 (2H, m). m/e
(ES.sup.+) 355 (MH.sup.+).
f) N-[2-(Piperidin-4-yl)phenyl]methanesulfonamide
Trifluoroacetate
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide
(488 mg) was dissolved in trifluoroacetic acid-dichloromethane
(10%, 50 mL) and stirred at room temperature for 2 h. The solvent
was evaporated under reduced pressure to give the title compound as
a colourless gum (501 mg), .delta..sub.H (CDCl.sub.3) 1.97 (4H, br
m), 3.03 (3H, s), 3.16 (2H, m), 3.48 (1H, m), 3.68 (2H, m),
7.25-7.43 (4H, m), 8.01 (1H, br s).
INTERMEDIATE 6
N-Methyl-N-[2-(piperidin-4-yl)phenyl]methanesulfonamide
Trifluoroacetate
a)
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]-N-methylmethanesulfonamide
Sodium hydride (60% dispersion in mineral oil, 73.4 mg) was added
to a solution of
N-[2-(1-t-butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide
(650 mg) in tetrahydrofuran (50 mL) and the mixture was stirred at
room temperature for 1 h. Methyl iodide (260 mg) was added and the
mixture was stirred at room temperature for 36 h. The solvent was
evaporated under reduced pressure, and the residue was partitioned
between water and ethyl acetate (100 mL). The organic layer was
separated, dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure to give the title compound as colorless solid (662
mg), .delta..sub.H (CDCl.sub.3) 1.48 (9H, s), 1.73 (2H, m), 1.88
(2H, m), 2.84 (2H, m), 2.97 (3H, s), 3.25 (3H, s), 3.33 (1H, m),
4.13 (2H, m), 7.21-7.36 (4H, m). m/e (ES.sup.+) 369 (MH.sup.+).
b) N-Methyl-N-[2-(piperidin-4-yl)phenyl]methanesulfonamide
Trifluoroacetate
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]-N-methylmethanesulfonamide
(662 mg) was dissolved in trifluoroacetic acid-dichloromethane
(10%, 50 mL) and stirred at room temperature 2 h. The solvent was
evaporated under reduced pressure to give the title compound as a
colourless gum (670 mg), m/e (ES.sup.+) 269 (MH.sup.+).
INTERMEDIATE 7
N-Phenyl-N-[(piperidin-4-yl)methyl]methanesulfonamide
Hydrochloride
a) 1-t-Butoxycarbonylpiperidine-4-carboxylic Acid
Di-t-butyldicarbonate (23.42 g, 107.3 mmol) in dichloromethane (100
mL) was added slowly to a mixture of 4-piperidinecarboxylic acid
(12.60 g, 97.6 mmol) and triethylamine (13.60 mL, 9.87 g, 97.6
mmol) in dichloromethane (50 mL) and the mixture was stirred at
room temperature for 18 h. N,N-Dimethylethylenediamine (3.46 mL,
2.87 g, 32.5 mmol) was added and the mixture was stirred at room
temperature for 30 min. Dichloromethane (100 mL) was added and the
mixture was washed with aqueous citric acid (10%, 2.times.200 mL),
dried (MgSO.sub.4) and the solvent was evaporated under reduced
pressure to give the title compound as a colorless solid (21.05 g,
94%), .delta..sub.H (250 MHz, CDCl.sub.3) 4.02 (2H, m), 2.86 (2H,
m), 2.49 (1H, m), 1.91 (2H, m), 1.64 (2H, m), and 1.46 (9H, s).
b) N-Phenyl-1-t-butoxycarbonylpiperidine-4-carboxamide
Triethylamine (10.04 mL, 7.28 g, 72 mmol) was added to stirred,
cooled (0.degree. C.) mixture of
1-t-butoxycarbonylpiperidine-4-carboxylic acid (6.87 g, 30 mmol),
aniline (2.73 mL, 2.79 g, 30 mmol) and
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (9.16 g, 36 mmol) in
dichloromethane (50 mL) and the mixture was stirred at room
temperature for 18 h. The solvent was evaporated under reduced
pressure, water (50 mL) was added and the mixture was extracted
with ethyl acetate (4.times.50 mL). The combined organic fractions
were washed with aqueous citric acid (10%, 2.times.50 mL), aqueous
sodium hydrogen carbonate (saturated, 2.times.50 mL) and brine (50
mL), dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with EtOAc/Hexane (40:60) to
give the title compound as a colorless foam (7.23 g, 79%),
.delta..sub.H (250 MHz, CDCl.sub.3) 7.51 (2H, d, J 7.6 Hz), 7.32
(2H, t, J 7.6 Hz), 7.26 (1H, br s), 7.11 (1H, t, J 7.6 Hz), 4.19
(2H, m), 2.78 (2H, m), 2.38 (1H, m), 1.90 (2H, m), 1.77 (2H, m),
and 1.47 (9H, s). m/e (ES.sup.+) 305 (MH.sup.+).
c) N-Phenyl-1-t-butoxycarbonylpiperidine-4-methylamine
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 57 mL, 57
mmol) was added to a stirred, cooled (0.degree. C.) solution
N-phenyl-1-t-butoxycarbonylpiperidine-4-carboxamide (5.78 g, 19
mmol) in tetrahydrofuran (95 mL) and the mixture was stirred at
room temperature for 18 h. Methanol (10 mL) was added and the
solvent was evaporated under reduced pressure. Potassium carbonate
(13.13 g, 95 mmol) and methanol (150 mL) were added and the mixture
was heated under reflux for 1 h. The mixture was cooled and the
solvent was evaporated under reduced pressure. Water (100 mL) was
added and the mixture was extracted with dichloromethane
(3.times.100 mL). The combined organic fractions were dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel, eluting with EtOAc/Hexane (20:80) to give the title compound
as a colorless solid (5.08 g, 92%), .delta..sub.H (250 MHz,
CDCl.sub.3) 7.18 (2H, t, J 7.6 Hz), 6.69 (1H, t, J 7.6 Hz), 6.59
(2H, d, J 7.6 Hz), 4.14 (2H, m), 3.73 (1H, br s), 3.03 (2H, d, J
6.2 Hz), 2.69 (2H, m), 1.79-1.55 (3H, m), 1.46 (9H, s), and 1.20
(2H, m).
d)
N-[(1-t-Butoxycarbonylpiperidin-4-yl)methyl]-N-phenylmethanesulfonamide
Methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) was added
dropwise to a stirred, cooled (0.degree. C.) solution of
N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.61 g, 9
mmol) and pyridine (1.09 mL, 1.07 g, 13.5 mmol) in dichloromethane
(50 mL) and the mixture was stirred at room temperature for 16 h.
The mixture was cooled in ice and 4-dimethylaminopyridine (220 mg,
1.8 mmol), pyridine (1.09 mL, 1.07 g, 13.5 mmol) and
methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) were added.
The mixture was stirred at room temperature for 24 h. The solvent
was evaporated under reduced pressure, aqueous sodium hydrogen
carbonate (saturated, 50 mL) was added and the mixture was
extracted with ethyl acetate (3.times.50 mL). The combined organic
fractions were washed with aqueous citric acid (10%, 2.times.50
mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine
(50 mL), dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was recrystallized from ethyl
acetate/hexane (2:1, 30 mL) to give the title compound as a
colorless solid (2.96 g, 89%), .delta..sub.H (250 MHz, CDCl.sub.3)
7.46-7.31 (5H, m), 4.06 (2H, m), 3.56 (2H, d, J 7.2 Hz), 2.85 (3H,
s), 2.60 (2H, m), 1.71 (2H, m), 1.57 (1H, m), 1.43 (9H, s), and
1.05 (2H, m).
e) N-Phenyl-N-[(piperidin-4-yl)methyl]methanesulfonamide
Hydrochloride
Methanolic hydrogen chloride (4M, 20 mL) was added to a stirred,
cooled (0.degree. C.) suspension
N-[(1-t-butoxycarbonylpiperidin-4-yl)methyl]-N-phenylmethanesulfonamide
(2.84 g, 7.7 mmol) in methanol (10 mL) and the mixture was stirred
at room temperature for 1 h. The solvent was evaporated under
reduced pressure to give the title compound as a tan foam (2.34 g,
100%), .delta..sub.H (250 MHz, d.sub.6 -DMSO) 8.90 (2H, br m),
7.45-7.33 (5H, m), 3.53 (2H, d, J 7.0 Hz), 3.19 (2H, m), 2.96 (3H,
s), 2.73 (2H, m), 1.80 (2H, m), 1.54 (1H, m), and 1.36 (2H, m).
INTERMEDIATE 8
N-Phenyl-N-[(piperidin-4-yl)methyl]acetamide Hydrochloride
a)
N-[(1-t-Butoxycarbonylpiperidin-4-yl)methyl]-N-phenylacetamide
Acetyl chloride (0.71 mL, 0.79 g, 10.0 mmol) was added dropwise to
a stirred, cooled (0.degree. C.) solution of
N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.42 g, 8.3
mmol), pyridine (1.01 mL, 0.99 g, 12.5 mmol) and
4-dimethylaminopyridine (204 mg, 1.7 mmol) in dichloromethane (50
mL) and the mixture was stirred at room temperature for 1 h.
Methanol (5 mL) was added and the solvent was evaporated under
reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 50
mL) was added and the mixture was extracted with ethyl acetate
(3.times.50 mL). The combined organic fractions were washed with
aqueous citric acid (10%, 2.times.50 mL), aqueous sodium hydrogen
carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO.sub.4)
and the solvent was evaporated under reduced pressure to give the
title compound as a colorless solid (2.73 g, 99%), .delta..sub.H
(250 MHz, CDCl.sub.3) 7.47-7.15 (5H, m), 4.06 (2H, br m), 3.62 (2H,
br m), 2.64 (2H, br m), 1.85 (3H, s), 1.66 (3H, m), 1.44 (9H, s),
and 1.20 (2H, m).
b) N-Phenyl-N-[(piperidin-4-yl)methyl]acetamide Hydrochloride
Methanolic hydrogen chloride (4M, 20 mL) was added to a stirred,
cooled (0.degree. C.) solution of
N-[(1-t-butoxycarbonylpiperidin-4-yl)methyl]-N-phenylacetamide
(2.72 g, 8.2 mmol) in methanol (10 mL) and the mixture was stirred
at room temperature for 1 h. The solvent was evaporated under
reduced pressure to give the title compound as a tan foam (2.17 g,
99%), .delta..sub.H (250 MHz, d.sub.6 -DMSO) 9.12-8.70 (2H, br m),
7.50-7.33 (5H, m), 3.57 (2H, d, J 7.1 Hz), 3.19 (2H, m), 2.75 (2H,
m), 1.73 (6H, m), and 1.37 (2H, m).
INTERMEDIATE 9
Spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-one]Hydrochloride
a) 1-Benzylspiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-one]
Trifluoroacetic acid (50 mL) was added to 2-aminobenzonitrile (6.81
g, 50 mmol) and 1-benzylpiperidin-4-one (10.41 g, 55 mmol) and the
mixture was heated under reflux for 8 h. The mixture was cooled and
the solvent was evaporated under reduced pressure. Water (300 mL)
was added and the pH was adjusted to 10.0 with aqueous sodium
hydroxide (4M). The solid was collected and dried in vacuo.
Methanol (200 mL) was added and the mixture was heated under reflux
for 1 h., cooled and refrigerated. The solid was collected and
dried in vacuo. The residue was recrystallized from ethanol-water
(80:20, 900 mL) to give the title compound as a colorless solid
(7.09 g, 46%), m.p. 224.degree.-246.degree. C. (Dec.),
.delta..sub.H (250 MHz, d.sub.6 -DMSO) 7.98 (1H, s), 7.57 (1H, d, J
7.7 Hz), 7.35-7.20 (6H, m), 6.82 (1H, d, J 7.7 Hz), 6.70 (1H, s),
6.64 (1H, t, J 7.7 Hz), 3.50 (2H, s), 2.49 (4H, m), and 1.78 (4H,
m).
b)
Spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-one]Hydrochloride
A suspension of palladium on carbon (10%, 1.8 g) in methanol (30
mL) was added to a solution of
1-benzylspiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-one] (5.53
g, 18 mmol) and formic acid (90%, 9 mL) in degassed methanol (150
mL). The mixture was stirred at room temperature for 72 h., further
palladium on carbon (10%, 0.9 g) in methanol (15 mL) and formic
acid (90%, 4.5 mL) were added and the mixture was stirred at room
temperature for a further 24 h. The mixture was filtered through
Hyflo and the solvent was evaporated under reduced pressure. The
residue was dissolved in ethanol (90 mL) and ethanolic hydrogen
chloride (5M, 4.32 mL) was added. The solvent was evaporated under
reduced pressure, propan-2-ol (100 mL) was added and the mixture
was heated under reflux for 1 h. The mixture was cooled and
refrigerated and the solid was collected and dried in vacuo to give
the title compound as a cream solid (3.72 g, 82%), .delta..sub.H
(250 MHz, d.sub.6 -DMSO) 9.28 (1H, br s), 8.88 (1H, br s), 8.37
(1H, s), 7.59 (1H, d, J 7.7 Hz), 7.28 (1H, t, J 7.7 Hz), 7.19 (1H,
s), 6.88 (1H, d, J 7.7 Hz), 6.70 (1H, t, J 7.7 Hz), 3.24 (4H, br
m), and 1.98 (4H, m). m/e (ES.sup.+) 218 (MH.sup.+).
INTERMEDIATE 10
N-[2-(Piperazin-1-yl)phenyl]methanesulfonamide
a) 1-Benzyl-4-(2-nitrophenyl)piperazine
Benzyl bromide (3.1 mL, 26 mmol) was added to a mixture of
1-(2-nitrophenyl)piperazine (4.91 g, 24 mmol) and potassium
carbonate (8.2 g, 59 mmol) in dimethylformamide (30 mL) and the
mixture was stirred at room temperature for 2 h. The solvent was
evaporated under reduced pressure and the residue was azeotroped
with xylene. The residue was diluted with ethyl acetate, washed
with brine (.times.3), dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with
EtOAc/Hexane (60:40) to give the title compound as an orange oil
(4.0 g, 57%). .delta..sub.H (250 MHz, CDCl.sub.3) 7.75 (1H, dd, J
1.6, 8.1 Hz), 7.46 (1H, dt, J 1.6, 7.3 Hz), 7.34-7.24 (5H, m), 7.12
(1H, dd, J 7.1, 8.3 Hz), 7.01 (1H, dt, J 1.2, 8.3 Hz), 3.57 (2H,
s), 3.10-3.05 (4H, m), and 2.63-2.58 (4H, m).
b) 1-(2-Aminophenyl)-4-benzylpiperazine
Tin (II) chloride (12.77 g, 67 mmol) was added to a solution of
1-benzyl-4-(2-nitrophenyl)piperazine (4.0 g, 13 mmol) in ethanol
(50 mL) and the mixture was heated at 70.degree. C. for 1 h. The
solvent was evaporated under reduced pressure and the residue was
diluted with ethyl acetate and washed with aqueous sodium hydroxide
(2M, 4.times.). The organic layer was dried (MgSO.sub.4) and the
solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel, eluting with
EtOAc/Hexane (80:20 increasing to 75:25) to give the title compound
as a pale yellow solid (2.61 g, 72%), .delta..sub.H (250 MHz,
CDCl.sub.3) 7.38-7.25 (5H, m), 7.03-6.89 (2H, m), 6.77-6.70 (2H,
m), 4.05-3.90 (2H, br s), 3.59 (2H, s), 2.96-2.92 (4H, m), and
2.65-2.55 (4H, br s).
c) N-[2-(4-Benzylpiperazin-1-yl)phenyl]methanesulfonamide
Methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added to a cooled
(0.degree. C.) solution of 1-(2-aminophenyl)-4-benzylpiperazine
(2.61 g, 9.8 mmol) and pyridine (0.95 mL, 11.7 mmol) in
dichloromethane (30 mL) and the mixture was stirred at room
temperature for 16 h. The solvent was evaporated under reduced
pressure and triethylamine (1.4 mL) was added. The mixture was
azeotroped with xylene, diluted with ethyl acetate and washed with
aqueous potassium carbonate (saturated, 3.times.). The organic
layer was dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH
(99:1) to give the title compound as yellow oil (2.83 g, 84%).
.delta..sub.H (250 MHz, CDCl.sub.3) 7.88-7.80 (1H, br s), 7.51 (1H,
dd, J 1.6, 8.0 Hz), 7.34-7.27 (5H, m), 7.25 (1H, dd, J 1.6, 7.5
Hz), 7.16 (1H, dt, J 1.6, 7.5 Hz), 7.07 (1H, dt, J 1.7, 7.6 Hz),
3.59 (2H, s), 3.04 (3H, s), 2.90-2.85 (4H, m), and 2.66-2.60 (4H,
br s).
d) N-[2-(Piperazin-1-yl)phenyl]methanesulfonamide
A solution of the product of
N-[2-(4-benzylpiperazin-1-yl)phenyl]methanesulfonamide (2.83 g, 8.2
mmol) in methanol (40 mL) was purged with nitrogen (0.25 hour).
Ammonium formate (1.55 g, 24.6 mmol), formic acid (0.31 mL, 8.21
mmol) and palladium on activated charcoal (0.5 g) were added. The
mixture was heated at reflux for 2 h., cooled, filtered, and the
solvent was evaporated under reduced pressure. The residue was
diluted with ethyl acetate and washed with aqueous potassium
carbonate (saturated, 3.times.). The organic layer was dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure
to give the title compound as a pale yellow crystalline solid
(1.196 g, 57%), .delta..sub.H (250 MHz, CDCl.sub.3) 7.52 (1H, dd, J
1.6, 8.0 Hz), 7.23-7.05 (4H, m), 3.06 (3H, s), 3.06-3.02 (4H, m),
2.85-2.78 (4H, m), and 1.80 (1H, br s).
INTERMEDIATE 11
4-[2-Methylphenyl]piperidine Hydrochloride
Tetrakis(triphenylphosphine)palladium (0) (100 mg) was added to a
degassed mixture of
1-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridin
e (1.32 g), 2-formylphenylboronic acid (850 mg), lithium chloride
(504 mg) and aqueous sodium carbonate (2N, 5.47 mL) in
1,2-dimethoxyethane (30 mL). The resulting solution was heated
under reflux for 3 h., cooled to room temperature and the solvent
was evaporated under reduced pressure. The residue was partitioned
between ethyl acetate and aqueous sodium carbonate (2M) and the
organic layer was separated, dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was dissolved in
ethanol, palladium on carbon (10%) was added and the mixture was
shaken under hydrogen (50 psi.) for 3 h. The mixture was filtered
through Hyflo, the solvent was evaporated under reduced pressure
and the residue was purified by MPLC on silica gel, eluting with
EtOAc/Hexane (5:95). The residue was dissolved in ethanolic
hydrogen chloride (50 mL) and stirred at room temperature for 30
min. The solvent was evaporated under reduced pressure to give the
title compound as a colorless solid (610 mg). m/e (ES.sup.+) 176
(MH.sup.+).
INTERMEDIATE 12
N-[2-(Piperazin-1-yl)phenylmethyl]methanesulfonamide
Hydrochloride
a) 2-[4-(t-Butoxycarbonyl)piperazin-1-yl]benzonitrile
Di-t-butyldicarbonate (2.62 g, 12 mmol) in 1,4-dioxane (8 mL) was
added to a mixture of 2-(piperazin-1-yl)benzonitrile (1.87 g, 10
mmol), sodium carbonate (2.65 g, 25 mmol) and 1,4-dioxane (2 mL) in
water (30 mL) and the mixture was stirred at room temperature for
22 h. Water (50 mL) was added and the mixture was extracted with
ethyl acetate (3.times.50 mL). The combined organic fractions were
washed with brine (50 mL), dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with CH.sub.2
Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1) to give the title compound
as a pale yellow oil (2.65 g, 92%), .delta..sub.H (250 MHz,
CDCl.sub.3) 7.59 (1H, d, J 7.8 Hz), 7.50 (1H, t, J 7.8 Hz), 7.05
(2H, m), 3.64 (4H, t, J 5.0 Hz), 3.15 (4H, t, J5.0 Hz), and 1.49
(9H, s).
b) 2-(4-t-Butoxycarbonylpiperazin-1-yl)phenylmethylamine
Platinum oxide (200 mg) was added to a solution of
2-[4-(t-butoxycarbonyl)piperazin-1-yl]benzonitrile (2.01 g, 7 mmol)
in ethanol-acetic acid (95:5, 35 mL) and the mixture was shaken
under hydrogen (50 psi) for 22 h, adding further platinum oxide (1
g) after 4 h. The mixture was filtered through Hyflo, further
ethanol (85 mL), acetic acid (15 mL) and platinum oxide (1 g) were
added and the mixture was shaken under hydrogen (50 psi) for 6 h.,
adding further platinum oxide (200 mg) after 2 h. and 4 h. The
mixture was filtered through Hyflo and the solvent was evaporated
under reduced pressure. Water (50 mL) was added, the pH was
adjusted to 10.0 with aqueous potassium carbonate (saturated) and
the mixture was extracted with ether (3.times.50 mL). The combined
organic fractions were dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure to give the crude title compound
as a pale yellow oil (2.03 g, 100%), .delta..sub.H (360 MHz,
CDCl.sub.3) 7.34-7.08 (4H, m), 3.91 (2H, s), 3.57 (4H, t, J 4.9
Hz), 2.87 (4H, t, J 4.9 Hz), 1.60 (2H, br s), and 1.49 (9H, s).
c)
N-[2-(4-t-Butoxycarbonylpiperazin-1-yl)phenylmethyl]methanesulfonamide
Methanesulfonyl chloride (0.186 mL, 275 mg, 2.4 mmol) was added
dropwise to a stirred, cooled (0.degree. C.) solution of
2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (0.58 g, 2
mmol) and pyridine (0.32 mL, 0.32 g, 4 mmol) in dichloromethane (10
mL) and the mixture was stirred at room temperature for 3 h.
Further methanesulfonyl chloride (0.046 mL, 69 mg, 0.6 mmol) was
added and the mixture was stirred at room temperature for 3 h.
Water (1 mL) was added and the solvent was evaporated under reduced
pressure. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and
water were added and the mixture was extracted with ethyl acetate
(3.times.20 mL). The combined organic fractions were washed with
aqueous citric acid (10%, 2.times.20 mL), aqueous sodium hydrogen
carbonate (saturated, 2.times.20 mL) and brine (20 mL), dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure.
The residue was purified by MPLC on silica gel, eluting with
CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1) to give the title
compound as a colorless solid (344 mg, 47%), .delta..sub.H (250
MHz, CDCl.sub.3) 7.33 (2H, m), 7.15 (2H, m), 5.80 (1H, br t, J 4.0
Hz), 4.40 (2H, d, J 4.0 Hz), 3.60 (4H, br t, J 3.4 Hz), 2.88 (4H,
t, J 3.4 Hz), 2.82 (3H, s), and 1.49 (9H, s). m/e (ES.sup.+) 370
(MH.sup.+).
d) N-[2-(Piperazin-1-yl)phenylmethyl]methanesulfonamide
Hydrochloride
Methanolic hydrogen chloride (4M, 2.5 mL) was added to a stirred,
cooled (0.degree. C.) suspension of
N-[2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethyl]methanesulfonamide
(330 mg, 0.89 mmol) in methanol (1 mL) and the mixture was stirred
at room temperature for 4 h. The solvent was evaporated under
reduced pressure to give the title compound as an off-white solid
(269 mg, 99%), .delta..sub.H (360 MHz, d.sub.6 -DMSO) 9.15 (2H, br
s), 7.44 (1H, d, J 7.6 Hz), 7.42 (1H, br t, J 5.6 Hz), 7.31 (1H, t,
J 7.6 Hz), 7.16 (2H, m), 4.22 (2H, d, J 5.6 Hz), 3.23 (4H, m), 3.06
(4H, m), and 2.92 (3H, s). m/e (ES.sup.+) 270 (MH.sup.+).
INTERMEDIATE 13
N-[2-(Piperazin-1-yl)phenylmethyl]acetamide Hydrochloride
a)
N-[2-(4-t-Butoxycarbonylpiperazin-1-yl)phenylmethyl]acetamide
Acetic anhydride (0.40 mL, 0.43 g, 4.2 mmol) was added to a
stirred, cooled (0.degree. C.) solution of
2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (1.02 g, 3.5
mmol), 4-dimethylaminopyridine (86 mg, 0.7 mmol) and pyridine (0.57
mL, 0.55 g, 7 mmol) in dichloromethane (10 mL) and the mixture was
stirred at room temperature for 1 h. Methanol (1 mL) was added and
the mixture was stirred at room temperature for 2 h. Aqueous sodium
hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added
and the mixture was extracted with dichloromethane (3.times.20 mL).
The combined organic fractions were dried (MgSO.sub.4) and the
solvent was evaporated under reduced pressure. The residue was
purified by MPLC on silica gel, eluting with CH.sub.2 Cl.sub.2
/MeOH/NH.sub.3 (Aq.) (99.5:0.5:0.05 increasing to 98:2:0.2) to give
the title compound as a colorless solid (681 mg, 58%),
.delta..sub.H (250 MHz, CDCl.sub.3) 7.28 (2H, m), 7.12 (2H, m),
6.26 (1H, br s), 4.55 (2H, d, J 5.6 Hz), 3.57 (4H, t, J 4.9 Hz),
2.86 (4H, t, J 4.9 Hz), 2.03 (3H, s), and 1.49 (9H, s). m/e
(ES.sup.+) 334 (MH.sup.+).
b) N-[2-(Piperazin-1-yl)phenylmethyl]acetamide Hydrochloride
Methanolic hydrogen chloride (4M, 5 mL) was added to a stirred,
cooled (0.degree. C.) suspension of
N-[2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethyl]acetamide (668
mg, 2 mmol) in methanol (2 mL) and the mixture was stirred at room
temperature for 4 h. The solvent was evaporated under reduced
pressure to give the title compound as a colorless foam (536 mg,
99%), .delta..sub.H (360 MHz, d.sub.6 -DMSO) 9.20 (2H, br s), 8.26
(1H, br t, J 5.8 Hz), 7.26 (2H, m), 7.12 (2H, m), 4.33 (2H, d, J
5.8 Hz), 3.22 (4H, m), 3.04 (4H, m), and 1.89 (3H, s). m/e
(ES.sup.+) 234 (MH.sup.+).
INTERMEDIATE 14
N,N-Dimethyl-[2-(piperazin-1-yl)phenyl]methylamine
Dihydrochloride
a)
N,N-Dimethyl-2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine
Sodium cyanoborohydride (1.10 g, 17.5 mmol) was added to a stirred,
cooled (0.degree. C.) mixture of
2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (1.02 g, 3.5
mmol) and aqueous formaldehyde (37%, 1.31 mL, 1.42 g, 17.5 mmol) in
acetonitrile (10 mL) and the mixture was stirred at room
temperature for 18 h. The solvent was evaporated under reduced
pressure, aqueous sodium hydrogen carbonate (saturated, 20 mL) and
water (10 mL) were added and the mixture was extracted with ethyl
acetate (3.times.20 mL). The combined organic fractions were washed
with aqueous sodium hydrogen carbonate (saturated, 3.times.20 mL)
and brine (20 mL), dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was purified by MPLC
on silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 (Aq.)
(99:1:0.1 increasing to 96:4:0.4) to give the title compound as a
colorless oil (400 mg, 36%), .delta..sub.H (250 MHz, CDCl.sub.3)
7.40 (1H, d, J 7.5 Hz), 7.25 (1H, t, J 7.5 Hz), 7.08 (2H, m), 3.56
(4H, t, J 5.0 Hz), 3.52 (2H, s), 2.91 (4H, t, J 5.0 Hz), 2.27 (6H,
s), and 1.49 (9H, s). m/e (ES.sup.+) 320 (MH.sup.+)
b) N,N-Dimethyl-[2-(piperazin-1-yl)phenyl]methylamine
Dihydrochloride
Methanolic hydrogen chloride (4M, 2.5 mL) was added to a stirred,
cooled (0.degree. C.) solution of
N,N-dimethyl-2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine
(392 mg, 1.2 mmol) in methanol (1 mL) and the mixture was stirred
at room temperature for 4 h. The solvent was evaporated under
reduced pressure to give the title compound as a colorless solid
(350 mg, 100%), .delta..sub.H (360 MHz, d.sub.6 -DMSO) 9.92 (1H, br
s), 9.26 (2H, br s), 7.62 (1H, d, J 7.7 Hz), 7.49 (1H, t, J 7.7
Hz), 7.31 (2H, m), 4.30 (2H, d, J 5.5 Hz), 3.31 (4H, m), 3.04 (4H,
m), 2.73 (3H, s), and 2.72 (3H, s). m/e (ES.sup.+) 220
(MH.sup.+).
EXAMPLE 1
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-keto-1-benzim
idazolinyl)piperidine Hydrochloride
a)
(S)-1-[2-t-Butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-ke
to-1-benzimidazolinyl)piperidine
Triethylamine (0.28 mL, 0.20 g, 2 mmol) was added to a stirred,
cooled (0.degree. C.) mixture of
(S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid
(prepared according to the method of Sugano. H, and Miyoshi. M, J.
Org. Chem 1976, 41, 2352) (364 mg, 1 mmol),
4-(2-keto-1-benzimidazolinyl)piperidine (217 mg, 1 mmol) and
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (305 mg, 2 mmol) in
dichloromethane (10 mL) and the mixture was stirred at room
temperature for 1h. Aqueous sodium hydrogen carbonate (saturated,
40 mL) and water (10 mL) were added and the mixture was extracted
with dichloromethane (3.times.50 mL). The combined organic
fractions were washed with aqueous citric acid (10%, 2.times.50
mL), aqueous sodium hydrogen carbonate (saturated, 2.times.50 mL)
and brine (50 mL), dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with CH.sub.2
Cl.sub.2 /MeOH (99:1) to give the title compound as a colorless
foam (318 mg, 56%). m/e (ES.sup.+) 563 (MH.sup.+).
b)
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-keto-1-benzi
midazolinyl)piperidine Hydrochloride
Methanolic hydrogen chloride (4M, 2 mL) was added to a solution of
(S)-1-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-ke
to-1-benzimidazolinyl)piperidine (298 mg, 0.53 mmol) in methanol (2
mL) and the mixture was stirred at room temperature for 5 h. The
solvent was evaporated under reduced pressure, dichloromethane (5
mL), triethylamine (0.148 mL, 107 mg, 1.06 mmol), benzaldehyde
(0.065 mL, 67 mg, 0.64 mmol) and magnesium sulfate (300 mg) were
added. The mixture was stirred at room temperature for 4 h.,
filtered and the solvent was evaporated under reduced pressure.
Methanol (5 mL) was added, the mixture was cooled to 0.degree. C.
and sodium borohydride (40 mg, 1.06 mmol) was added. The mixture
was stirred at room temperature for 1 h., aqueous sodium hydrogen
carbonate (saturated, 20 mL) and water (10 mL) were added and the
mixture was extracted with dichloromethane (3.times.20 mL). The
combined organic fractions were dried (MgSO.sub.4) and the solvent
was evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with CH.sub.2
Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1 increasing to 95:5:0.5).
The residue was dissolved in methanol (5 mL), cooled to 0.degree.
C. and methanolic hydrogen chloride (1M, 0.44 mL) was added. The
solvent was evaporated under reduced pressure and the residue was
triturated with ether (5 mL). The solid was collected and dried in
vacuo to give the title compound as a colorless solid (212 mg,
68%), m.p. 148.degree.-151.degree. C. Found: C, 57.18; H, 5.29; N,
9.27. C.sub.29 H.sub.30 Cl.sub.2 N.sub.4 O.sub.3.HCl.H.sub.2 O
requires: C, 57.29; H, 5.47; N, 9.22%. m/e (ES.sup.+) 553
(MH.sup.+).
The following compounds were prepared from
(S)-2-t-butoxycarbonylamino-3-benzyloxypropionic acid or
(S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid
(prepared according to the method of Sugano. H, and Miyoshi. M, J.
Org. Chem 1976, 41, 2352) and the appropriate substituted
piperidine or piperazine, followed by reductive amination with
benzaldehyde or 3,4-dichlorobenzaldehyde, according to the method
of Example 1:
References:
N-(4-Phenylpiperidin-4-yl)acetamide (EP512901A1)
Spiro[1H-indene-1,4'-piperidine]Hydrochloride (J. Med. Chem. 1992,
35, 2033-2039)
2,3-Dihydrospiro[1H-indene-1,4'-piperidine]Hydrochloride (J. Med.
Chem. 1992, 35, 2033-2039)
Spiro[piperidine-4,6'-[6'H]thieno[2,3-b]thiopyran]-4'(5'H)-one]Hydrochlorid
e (U.S. Pat. No. 5,206,240, Example 2A)
(RS)-Spiro[2H-1-benzopyran-2,3'-piperidine]-4-(3H)-one
Hydrochloride (U.S. Pat. No. 5,206,240, Example 52B)
6-methoxyspiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one
Hydrochloride (U.S. Pat. No. 5,206,240, Example 231)
Spiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one Hydrochloride
(U.S. Pat. No. 5,206,240, Example 67A)
EXAMPLE 2
(S)-1'-[3-Benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]spiro[1H-indene-1,
4'-piperidine]Hydrochloride
Found C, 62.51; H, 560; N, 4.95. C.sub.30 H.sub.30 Cl.sub.2 N.sub.2
O.sub.2.HCl.H.sub.2 O requires: C, 62.56; H, 5.77; N, 4.86%. m/e
(CI.sup.+) 521 (MH.sup.+).
EXAMPLE 3
(S)-N-({1-[3-Benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide Hydrochloride
Found C, 57.90; H, 6.11; N, 6.54. C.sub.31 H.sub.35 Cl.sub.2
N.sub.3 O.sub.3.HCl.2H.sub.2 O requires: C, 58.08; H, 6.23; N,
6.55%. m/e (CI.sup.+) 568 (MH.sup.+).
EXAMPLE 4
(S)-1-[3-Benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-(methanesulfonam
idomethyl)-4-phenylpiperidine Hydrochloride
Found C, 55.20; H, 5.97; N, 6.99. C.sub.30 H.sub.35 Cl.sub.2
N.sub.3 O.sub.4 S.HCl.0.5H.sub.2 O requires: C, 55.43; H, 5.74; N,
6.46%. m/e (CI.sup.+) 604 (MH.sup.+).
EXAMPLE 5
(S)-1-[3-Benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperidine
Hydrochloride
Found C, 62.95; H, 5.69; N, 4.74. C.sub.28 H.sub.30 Cl.sub.2
N.sub.2 O.sub.2.HCl requires: C, 62.99; H, 5.85; N, 5.25%. m/e
(CI.sup.+) 497 (MH.sup.+).
EXAMPLE 6
(S)-N-{1-[3-Benzyloxy-2-(3,4-dichlorobenzylamino)propionyl]-4-phenylpiperid
in-4-yl}acetamide Hydrochloride
Found C, 59.74; H, 5.70; N, 6.49. C.sub.30 H.sub.33 Cl.sub.2
N.sub.3 O.sub.3.HCl.0.75H.sub.2 O requires: C, 59.60; H, 5.91; N,
6.95%. m/e (CI.sup.+) 554 (MH.sup.+).
EXAMPLE 7
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methoxyphenyl
)piperazine Hydrochloride
Found C, 57.90; H, 5.64; N, 7.09. C.sub.28 H.sub.31 Cl.sub.2
N.sub.3 O.sub.3.HCl.H.sub.2 O requires: C, 57.69; H, 5.88; N,
7.20%. m/e (ES.sup.+) 528 (MH.sup.+).
EXAMPLE 8
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-pyridyl)piper
azine Hydrochloride
.delta..sub.H (d.sub.6 -DMSO) 3.6-3.9 (8H, br m), 3.84 (2H, d, J
4.0 Hz), 4.13 (2H br m), 4.54 (2H, d, J 4.0 Hz), 4.73 (1H, br s),
6.90 (1H, br s), 7.30 (1H, br m), 7.32 (1H, m), 7.40 (2H, m), 7.51
(2H, m), 7.6 (2H, m), 7.73 (1H br m), 8.09 (1H, m). m/e (ES.sup.+)
499 (MH.sup.+).
EXAMPLE 9
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-chlorophenyl)
piperazine Hydrochloride
Found C, 56.70; H, 4.99; N, 7.10. C.sub.27 H.sub.28 Cl.sub.3
N.sub.3 O.sub.2.HCl requires: C, 56.96; H, 5.13; N, 7.38%. m/e
(ES.sup.+) 532 (MH.sup.+).
EXAMPLE 10
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-cyano-4-phenylpi
peridine Hydrochloride
M.p. 219.degree.-222.degree. C. Found: C, 61.91; H, 5.22; N, 7.55.
C.sub.29 H.sub.29 Cl.sub.2 N.sub.3 O.sub.2.HCl.0.25H.sub.2 O
requires: C, 61.82; H, 5.46; N, 7.46%. m/e (ES.sup.+) 522
(MH.sup.+).
EXAMPLE 11
(S)-Methyl
1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperidine-4-
carboxylate
.delta..sub.H (CDCl.sub.3) 1.20-2.0 (4H, m), 2.36-2.58 (2H, m),
2.81-3.17 (2H m), 3.45-3.62 (2H, m), 3.67 (3H, s), 3.68-3.79) (2H,
m), 4.29 (2H, d, J 6.0 Hz), 4.70 (1H, m), 6.90 (1H, br s),
6.96-7.41 (12H, m). m/e (ES.sup.+) 555 (MH.sup.+).
EXAMPLE 12
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methylphenyl)
piperazine Dihydrochloride
Found: C, 55.30; H, 5.71; N, 6.91. C.sub.28 H.sub.31 Cl.sub.2
N.sub.3 O.sub.2.2HCl.H.sub.2 O requires: C, 55.73; H, 5.85; N,
6.96%. m/e (ES.sup.+) 512 (MH.sup.+).
EXAMPLE 13
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-nitrophenyl)p
iperazine Sesquihydrochloride
Found: C, 52.62; H, 5.15; N, 8.96. C.sub.27 H.sub.28 Cl.sub.2
N.sub.4 O.sub.4.1.5HCl.H.sub.2 O requires: C, 52.63; H, 5.15; N,
9.09%. m/e (ES.sup.+) 543 (MH.sup.+).
EXAMPLE 14
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(pyrimidin-2-yl)
piperazine Dihydrochloride
Found: C, 50.08; H, 5.21; N, 11.42. C.sub.25 H.sub.27 Cl.sub.2
N.sub.5 O.sub.2.2HCl.1.5H.sub.2 O requires: C, 50.02; H, 5.37; N,
11.66%. m/e (ES.sup.+) 500 (MH.sup.+).
EXAMPLE 15
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methoxyphenyl
)piperidine Hydrochloride
.delta..sub.H (d.sub.6 -DMSO) 1.08-1.12 (2H, m), 1.64 (1H, m), 1.76
(1H m), 2.66-2.69 (1H, m), 3.02--3.10 (2H, br m), 3.33 (3H, s) 3.77
(2H, d, J 11.0 Hz), 3.84-3.87 (3H, m), 4.12-4.20 (2H, m), 4.48-4.62
(3H, m) 6.82 (1H, m), 6.97 (1H, m), 7.00 (1H, m), 7.22 (1H, m),
7.34 (3H, m), 7.51 (2H m), 7.67 (2H m). m/e (ES.sup.+) 527
(MH.sup.+).
EXAMPLE 16
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(methanesulfo
namido)phenyl]piperidine Hydrochloride
.delta..sub.H (d.sub.6 -DMSO) 1.19-1.23 (2H, m), 1.76 (1H, m),
2.51-2.70 (1H m), 2.99 (3H, s), 3.04-3.10 (2H, m), 3.89 (3H, m),
4.13-4.21 (2H, m), 4.50 (2H, s), 4.52-4.61 (2H, m), 6.89 (1H, br
s), 7.20-7.68 (12H, m). m/e (ES.sup.+) 590 (MH.sup.+).
EXAMPLE 17
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-{2-[N-(methyl)me
thanesulfonamido]phenyl}piperidine Hydrochloride
.delta..sub.H (d.sub.6 -DMSO) 1.22-1.77 (4H, m), 2.71 (2H, m), 3.03
(3H, s), 3.16 (3H, s), 3.87 (3H, m), 4.11 (2H, m), 4.17 (1H, m),
4.49-4.60 (4H, m), 7.25-7.69 (12H, m). m/e (ES.sup.+) 604
(MH.sup.+).
EXAMPLE 18
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(methanesulfonam
idomethyl)-4-phenylpiperidine Hydrochloride
M.p. 165.degree.-167.degree. C. Found: C, 55.43; H, 5.46; N, 6.34.
C.sub.30 H.sub.35 Cl.sub.2 N.sub.3 O.sub.4 S.HCl.0.5H.sub.2 O
requires: C, 55.43; H, 5.74; N, 6.46%. m/e (ES.sup.+) 604
(MH.sup.+).
EXAMPLE 19
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(N-phenylmethane
sulfonamidomethyl)piperidine Hydrochloride
M.p. 190.degree.-192.degree. C. Found: C, 55.11; H, 5.86; N, 6.42.
C.sub.30 H.sub.35 Cl.sub.2 N.sub.3 O.sub.4 S.HCl.0.5H.sub.2 O
requires: C, 55.43; H, 5.74; N, 6.46%. m/e (ES.sup.+) 604
(MH.sup.+).
EXAMPLE 20
(S)-N-({1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperi
din-4-yl}methyl)acetamide Hydrochloride
M.p. 165.degree.-167.degree. C. Found: C, 61.10; H, 6.19; N, 6.72.
C.sub.31 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3.HCl.0.25H.sub.2 O
requires: C, 61.09; H, 6.04; N, 6.89%. m/e (ES.sup.+) 568
(MH.sup.+).
EXAMPLE 21
(S)-N-({1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperidin-4-yl}
methyl)-N-phenylacetamide Hydrochloride
M.p. 108.degree.-110.degree. C. Found: C, 61.17; H, 5.97; N, 6.91.
C.sub.31 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3.HCl requires: C, 61.54;
H, 6.00; N, 6.95%. m/e (ES.sup.+) 568 (MH.sup.+).
EXAMPLE 22
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
2'(1'H)-quinazolin]-4'(3'H)-one]Hydrochloride
M.p. 145.degree.-147.degree. C. Found: C, 57.95; H, 5.26; N, 8.94.
C.sub.29 H.sub.30 Cl.sub.2 N.sub.4 O.sub.3.HCl.0.6H.sub.2 O
requires: C, 57.98; H, 5.40; N, 9.33%. m/e (ES.sup.+) 553
(MH.sup.+).
EXAMPLE 23
(S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-2,3-dihydrospiro[
1H-indene-1,4'-piperidine]Hydrochloride
M.p. 207.degree.-209.degree. C. Found: C, 64.30; H, 5.72; N, 5.04.
C.sub.30 H.sub.32 Cl.sub.2 N.sub.2 O.sub.2.HCl requires: C, 64.35;
H, 5.94; N, 5.00%. m/e (ES.sup.+) 523 (MH.sup.+).
EXAMPLE 24
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-cyanophenyl)p
iperazine Sesquihydrochloride
Found: C, 58.58; H, 4.97; N, 9.78. C.sub.28 H.sub.28 Cl.sub.2
N.sub.4 O.sub.2.1.5 HCl requires: C, 58.17; H, 5.14; N, 9.69%. m/e
(ES.sup.+) 523 MH.sup.+).
EXAMPLE 25
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methanesulfon
amidophenyl)piperazine Dihydrochloride
Found: C, 50.49; H, 5.20; N, 8.19. C.sub.28 H.sub.32 Cl.sub.2
N.sub.4 O.sub.4 S.2HCl requires: C, 50.61; H, 5.16; N, 8.43%. m/e
(ES.sup.+) 591 (MH.sup.+).
EXAMPLE 26
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[piperidine-4,
6'-[6'H]thieno[2,3-b]thiopyran]-4'(5'H)-one]Hydrochloride
M.p. 172.degree.-174.degree. C. Found: C, 54.54; H, 4.58; N, 4.36.
C.sub.28 H.sub.28 Cl.sub.2 N.sub.2 O.sub.3 S.sub.2.HCl.0.25H.sub.2
O requires: C, 54.55; H, 4.82; N, 4.54%. m/e (ES.sup.+) 575
(MH.sup.+).
EXAMPLE 27
(2S,
3'RS)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benz
opyran-2,3'-piperidine]-4-(3H)-one Hydrochloride
M.p. 99.degree.-101.degree. C. Found: C, 60.33; H, 5.15; N, 4.40.
C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.4.HCl.0.5H.sub.2 O
requires: C, 60.16; H, 5.39; N, 4.68%. m/e (ES.sup.+) 553
(MH.sup.+).
EXAMPLE 28
(S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-6-methoxyspiro[2H
-1-benzopyran-2,4'-piperidin]-4-(3H)-one Hydrochloride
M.p. 184.degree.-186.degree. C. Found: C, 59.68; H, 5.46; N, 4.44.
C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5.HCl requires: C, 60.06;
H, 5.37; N, 4.52%. m/e (ES.sup.+) 583 (MH.sup.+).
EXAMPLE 29
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-methylphenyl)
piperidine
.delta..sub.H (CDCl.sub.3) 1.49-1.67 (4H, m), 2.32 (3H, s), 2.65
(1H, m), 2.93 (2H, m), 3.52-2.70 (2H, m), 3.79-3.70 (2H, m), 4.44
(2H, s), 4.70 (2H, s), 4.83 (1H, m), 7.11-7.47 (12H, m). m/e
(ES.sup.+) 511 (MH.sup.+).
EXAMPLE 30
(S)-Ethyl-2-{4-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperazin-
1-yl}ethanoate Dihydrochloride
M.p. 208.degree.-210.degree. C. Found: C, 51.40; H, 5.92; N, 7.15.
C.sub.25 H.sub.31 Cl.sub.2 N.sub.3 O.sub.4.2HCl requires: C, 51.65;
H, 5.72; N, 7.23%. m/e (ES.sup.+) 508 (MH.sup.+).
EXAMPLE 31
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(methanesulfo
namidomethyl)phenyl]piperazine Hydrochloride
M.p. 112.degree.-114.degree. C. Found: C, 52.69; H, 5.46; N, 8.40.
C.sub.29 H.sub.34 Cl.sub.2 N.sub.4 O.sub.4 S.HCl.H.sub.2 O
requires: C, 52.77; H, 5.65; N, 8.49%. m/e (ES.sup.+) 605
(MH.sup.+).
EXAMPLE 32
(S)-N-(2-{4-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]piperazin-1-y
l}phenylmethyl)acetamide Dihydrochloride
M.p. 122.degree.-124.degree. C. Found: C, 55.86; H, 5.76; N, 8.62.
C.sub.30 H.sub.34 Cl.sub.2 N.sub.4 O.sub.3.2HCl requires: C, 56.09;
H, 5.65; N, 8.72%. m/e (ES.sup.+) 569 (MH.sup.+).
EXAMPLE 33
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-[2-(dimethylamin
omethyl)phenyl]piperazine Dihydrochloride
M.p. 226.degree.-228.degree. C. Found: C, 56.43; H, 6.12; N, 8.99.
C.sub.30 H.sub.36 Cl.sub.2 N.sub.4 O.sub.2.2HCl.0.5H.sub.2 O
requires: C, 56.52; H, 6.17; N, 8.79%. m/e (ES.sup.+) 555
(MH.sup.+).
EXAMPLE 34
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-hydroxymethyl-4-
phenylpiperidine
Lithium borohydride (5.0 mg) was added to a stirred solution of
(S)-methyl
1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperidin-4-c
arboxylate (100 mg) in toluene (5.0 mL) and tetrahydrofuran (5.0
mL). The resulting solution was warmed to reflux for 3 h., cooled
to room temperature and the solvent was evaporated under reduced
pressure. The residue was partitioned between ethyl acetate and
aqueous ammonium chloride (saturated) and the organic layer was
separated, dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by MPLC on silica gel,
eluting with CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1) to
give the title compound as a colorless solid (26 mg), .delta..sub.H
(CDCl.sub.3) 1.69-1.82 (5H, m), 2.41-2.61 (4H, m), 3.15-3.21 (2H
m), 3.44 (2H, s), 3.53-3.68 (4H, m), 4.34 (1H br s), 6.98-7.46
(12H, m). m/e (ES.sup.+) 527 (MH.sup.+).
EXAMPLE 35
(S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidin]-4-(3H)-one Hydrochloride
a)
(S)-1'-[2-t-Butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2
H-1-benzopyran-2,4'-piperidin]-4-(3H)-one
Triethylamine (0.50 mL, 0.36 g, 3.6 mmol) was added to a stirred,
cooled (0.degree. C.) mixture of
(S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid
(364 mg, 1 mmol), spiro[2H-1-benzopyran-2,4'-piperidin]-4-(3H)-one
hydrochloride (U.S. Pat. No. 5,206,240, Example 67A) (254 mg, 1
mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(230 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) in
dimethylformamide (5 mL) and the mixture was stirred at room
temperature for 2 h. Aqueous sodium hydrogen carbonate (saturated,
20 mL) and water (10 mL) were added and the mixture was extracted
with ethyl acetate (3.times.20 mL). The combined organic fractions
were washed with aqueous citric acid (10%, 2.times.20 mL), aqueous
sodium hydrogen carbonate (saturated, 2.times.20 mL) and brine (20
mL), dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH
(99.5:0.5 increasing to 98:2) to give the title compound as a
colorless foam (248 mg, 44%). m/e (ES.sup.+) 563 (MH.sup.+).
b)
(S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzop
yran-2,4'-piperidine]-4-(3H)-one Hydrochloride
Methanolic hydrogen chloride (4M, 2 mL) was added to a stirred,
cooled (0.degree. C.) solution of
(S)-1'-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2
H-1-benzopyran-2,4'-piperidine]-4-(3H)-one (243 mg, 0.43 mmol) in
methanol (2 mL) and the mixture was stirred at room temperature for
5 h. The solvent was evaporated under reduced pressure,
dichloromethane (5 mL), triethylamine (0.120 mL, 87 mg, 0.86 mmol),
benzaldehyde (0.052 mL, 55 mg, 0.52 mmol) and magnesium sulfate
(300 mg) were added. The mixture was stirred at room temperature
for 4 h., filtered and the solvent was evaporated under reduced
pressure. Methanol (5 mL) and sodium cyanoborohydride (54 mg, 0.86
mmol) were added. The mixture was stirred at room temperature for 1
h., aqueous sodium hydrogen carbonate (saturated, 20 mL) and water
(10 mL) were added and the mixture was extracted with
dichloromethane (3.times.20 mL). The combined organic fractions
were dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. Methanol (25 mL) was added and the volume was
reduced to 10 mL by distillation. The remaining solvent was
evaporated under reduced pressure and the residue was purified by
flash column chromatography on silica gel, eluting with CH.sub.2
Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1 increasing to 97:3:0.3).
The residue was dissolved in methanol (5 mL), cooled to 0.degree.
C. and methanolic hydrogen chloride (1M, 0.23 mL) was added. The
solvent was evaporated under reduced pressure and the residue was
triturated with ether (5 mL). The solid was collected and dried in
vacuo to give the title compound as a colorless solid (126 mg,
50%), mp. 173.degree.-175.degree. C. Found: C, 59.92; H, 5.14; N,
4.32. C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.4.HCl.0.5H.sub.2 O
requires: C, 60.16; H, 5.39; N, 4.68%. m/e (ES.sup.+) 553
(MH.sup.+).
EXAMPLE 36
(2S,
4'RS)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-3,4-dihydrospi
ro[2H-1-benzopyran-2,4'-piperidine]-4-ol Hydrochloride
Methanolic hydrogen chloride (4M, 8 mL) was added to a stirred,
cooled (0.degree. C.) solution of
(S)-1'-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2
H-1-benzopyran-2,4'-piperidine]-4-(3H)-one (899 mg, 1.6 mmol) in
methanol (4 mL) and the mixture was stirred at room temperature for
16 h. The solvent was evaporated under reduced pressure,
dichloromethane (10 mL), triethylamine (0.44 mL, 0.32 g, 3.2 mmol),
benzaldehyde (0.195 mL, 203 mg, 1.9 mmol) and magnesium sulfate
(1.0 g) were added. The mixture was stirred at room temperature for
4 h., filtered and the solvent was evaporated under reduced
pressure. Methanol (10 mL) was added and the mixture was cooled in
ice. Sodium borohydride (121 mg, 3.2 mmol) was added and the
mixture was stirred at 0.degree. C., adding further sodium
borohydride (121 mg, 3.2 mmol) after 1 h. and 2 h. The mixture was
stirred at room temperature for 16 h., aqueous sodium hydrogen
carbonate (saturated, 40 mL) and water (20 mL) were added and the
mixture was extracted with dichloromethane (3.times.40 mL). The
combined organic fractions were dried (MgSO.sub.4) and the solvent
was evaporated under reduced pressure. The residue was dissolved in
ethanol (10 mL) and cooled in ice. Sodium borohydride (121 mg, 3.2
mmol) was added and the mixture was stirred at 0.degree. C., adding
further sodium borohydride (121 mg, 3.2 mmol) after 2 h., 4 h. and
6 h. The mixture was stirred at room temperature for 14 h., aqueous
sodium hydrogen carbonate (saturated, 40 mL) and water (20 mL) were
added and the mixture was extracted with dichloromethane
(3.times.40 mL). The combined organic fractions were dried
(MgSO.sub.4) and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel, eluting with CH.sub.2 Cl.sub.2 /MeOH/NH.sub.3 (Aq.) (99:1:0.1
increasing to 98:2:0.2) to give (2S,
4'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-3,4-dihydrospi
ro[2H-1-benzopyran-2,4'-piperidine]-4-ol as a colorless foam (491
mg, 55%), .delta..sub.H (CHCl.sub.3) 7.43-6.82 (12H, m), 4.92-4.34
(4H, m), 3.84-3.00 (8H, m), and 2.15-1.14 (8H, m). A sample (203
mg, 0.37 mmol) was dissolved in ethanol (5 mL), cooled to 0.degree.
C. and ethanolic hydrogen chloride (5M, 0.088 mL) was added. The
solvent was evaporated under reduced pressure and the residue was
triturated with ether (10 mL). The solid was collected and dried in
vacuo to give the title compound as a colorless solid (218 mg,
100%), m.p. 116.degree.-118.degree. C. Found: C, 60.68; H, 5.77; N,
4.68. C.sub.30 H.sub.32 Cl.sub.2 N.sub.2 O.sub.4.HCl requires: C,
60.87; H, 5.62; N, 4.73%. m/e (ES.sup.+) 555 (MH.sup.+).
EXAMPLE 37
(S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopy
ran-2,4'-piperidine]Hydrochloride
A mixture of (2S,
4'RS)-1'-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-3,4-dihydrospi
ro[2H-1-benzopyran-2,4'-piperidine]-4-ol (278 mg, 0.5 mmol) and
p-toluenesulfonic acid monohydrate (114 mg, 0.6 mmol) in toluene
was heated under reflux for 30 min. The mixture was cooled and the
solvent was evaporated under reduced pressure. Aqueous sodium
hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added
and the mixture was extracted with dichloromethane (3.times.20 mL).
The combined organic fractions were dried (MgSO.sub.4), the solvent
was evaporated under reduced pressure and the residue was purified
by MPLC on silica gel, eluting with CH.sub.2 Cl.sub.2
/MeOH/NH.sub.3 (Aq.) (99:1:0.1). The residue was dissolved in
ethanol (5 mL), cooled to 0.degree. C. and ethanolic hydrogen
chloride (5M, 0.098 mL) was added. The solvent was evaporated under
reduced pressure and the residue was triturated with ether (10 mL).
The solid was collected and dried in vacuo to give the title
compound as a colorless solid (225 mg, 78%), m.p.
220.degree.-222.degree. C. Found: C, 62.74; H, 5.11; N, 4.83.
C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.3.HCl requires: C, 62.78;
H, 5.44; N, 4.88%. m/e (ES.sup.+) 537 (MH.sup.+).
EXAMPLE 38
(S)-1-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-aminophenyl)p
iperazine Dihydrochloride
Tin (II) chloride (1.79 g, 9.45 mmol) was added to a solution of
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-nitrophenyl)
piperazine (1.03 g, 1.89 mmol) in ethanol (15 mL) and the mixture
was stirred at 70.degree. C. for 1 h. The solvent was evaporated
under reduced pressure and the residue was diluted with ethyl
acetate and washed with aqueous sodium hydroxide (2M, 3 x). The
organic layer was dried (MgSO.sub.4) and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with CH.sub.2 Cl.sub.2
/MeOH/NH.sub.3 (Aq.) (99:1:0.1) to give
(S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-aminophenyl)
piperazine was a yellow oil (678 mg, 70%). A sample (70 mg) was
dissolved in methanolic hydrogen chloride and the solvent was
evaporated under reduced pressure. The residue was dissolved in
acetonitrile/water (1:1) and freeze-dried to give the title
compound as a colorless solid (70 mg); Found: C, 54.06; H, 5.42; N,
9.20. C.sub.27 H.sub.30 Cl.sub.2 N.sub.4 O.sub.2.2HCl.0.5H.sub.2 O
requires: C, 54.47; H, 5.59; N, 9.41%. m/e (ES.sup.+) 513
(MH.sup.+).
* * * * *